3-substituted 6alpha,beta-alkyl-cyclopenta(f)(1)benzopyrans and-naphto(2,1-b)pyrans

ABSTRACT

STEREO-SPECIFIC TOTAL SYNTHESIS OF STEROIDAL MATERIALS. 7-SUBSTITUTED 3-OXO-1-HEPTENES OR VARIANTS THEREOF ARE REACTED WITH 2-ALKYLCYCLOALKANE 1,3-DIONES YIELDING 3-SUBSTITUTED 6AB-ALKYL-CYCLOPENTA(F)(1)BENZOPYRANS OR NAPHTHO(2,1-B)PYRANS. THESE AE THEN SUBJECTED TO A SELECTIVE CATALYTIC HYDROGENATION FOLLOWED BY AN INTRODUCTION OF A HYDROXY, ALKOXY OR ACYLOXY GROUP AT THE 4A-POSITION TO PRODUCED A 3-SUBSTITUTED 6AB,4A-HYDROXY, ALKOXY OR ACYLOXY PERHYDROCYCLOPENTA(F)(1)BENZOYPRAN OR PERHYDRO NAPHTHO(2,1-B)PYRAN. THESE LATTER COMPOUNDS ARE THEN CONVERTED INTO 4- OR 5-(3-OXOALKYL)PERHYDROINDENE-5ONES OR PERHYDRONAPHTHALENE-6-ONES WHICH IN TURN CAN BE CONVERTED TO KNOWN STEROIDAL MATERIALS BY KNOWN METHODS.

fUnitedStates Patent Office 1 3,816,458 Patented June 11., 1,974

3,816,458 S-SUBSTITUTED Ga,B-ALKYL-'CYCLOPENTA[I][1] BENZOPYRANS AND-NAPHTHO[2,1-b]PYRANS Gabriel Saucy, Essex Fells, NJ., assignor toHoifmann- La Roche Inc., Nutley, NJ.

No Drawing. Continuation-impart of application Ser. No. 679,989, Nov. 2,1967, now Patent No. 3,544,598, which is a continuation-in-part ofabandoned application .Ser. No. 633,730, Apr. 26, 1967, which is acontinuation-in-part of abandoned application Ser. No.

604,124, Dec. 23, 1966, which in turn is a continuationin-part ofabandoned application Ser. No. 549,816, May 13, 1966. This applicationalso a continuation-in-part of abandoned application Ser. No. 813,693,Apr. 4,

1969. This application July 22, 1970, Ser. No. 57,372

Int. Cl. C07d 13/04 US. Cl. 260-3403 52 Claims ABSTRACT OF THEDISCLOSURE 'naphtho[2,1-b]pyran. These latter compounds are thenconverted into 4- or 5-(3-oxoalkyl)perhydroindene-S- ones orperhydronaphthalene-6-ones which in turn can be converted toknownsteroidal materials by known methods.

RELATED APPLICATIONS This application is a continuation-in-part ofapplicants co-pending application Ser. No. 679,989, filed Nov. 2, 1967now US. Pat. No. 3,544,598 which is a continuationin-part of applicantsco-pending application Ser. No. 633,730, filed Apr. 26, 1967, nowabandoned which was filed as a continuation-in-part of applicantsco-pending application Ser. No. 604,124, 'filed Dec. 23, 1966, nowabandoned which was filed as a continuation-in-part of applicantsco-pending application Ser. No. 549,816, filed May 13, 1966 nowabandoned. This application is also a continuation-in-part'of co-pendingapplication Ser. No.

813,693, filed Apr. 4, 1969, now abandoned, inventors Gabriel Saucy andMichael Rosenberger, entitled, Preparation of 3-Oxo-l9-Nor-A -SteroidsFrom -[3-Substituted Alkyl]-DesA Steroids.

BACKGROUND OF THE INVENTION Cyclopenta[f] [l]-benzopyrans and7H-naphtho[2,1-b] pyrans are valuable as intermediates in the totalsynthesis of steroids. Total syntheses utilizing these compounds asintermediates are described in US. patent applications of Gabriel Saucy:Ser. No. 549,816, filed May 13, 1966; Ser. No. 604,124 filed Dec. 23,1966; Ser. No. 633,730, filed Apr. 26, 1967. Other related applicationsinclude Ser. No. 633,693, filed Apr. 26, 1967. All the above cases arenow abandoned.

DETAILED DESCRIPTION OF INVENTION This invention is concerned withcertain polycyclic compounds and with processes for their synthesis.More particularly, this invention relates to novel cyclopenta[f][1]-benzopyrans and 7H-naphtho[2,1-b]pyrans, and to methods for theirproduction. These compounds are useful as intermediates in syntheses ofsteroids and D- homosteroids, respectively. In syntheses of steroidalmaterials steric considerations are of great significance. The

most used steroidal compounds are those having a C/D- trans ringjunction .with' the substituent in the 13 -position being-in thefi-stereoconfiguratiouThe present invention provides a facile totalsynthesis of. -13l9-C/D:tra,nssteroidal materials. This .desirable.result is obtained via a. unique asymmetric induction with opticalspecificitypreserved in subsequent reaction steps. 1 .i viz: gr:

In a major aspect,-this invention is concerned with novelcyclopenta[f][1]benzopyrans having, the. tricyclic "nucleus and novelnaphtho[2,1-b]pyrans having the tricyclic nucleus wherein Y is hydrogen;an alkyl group of from 1 to 6 carbons; or a group of the formula 5 2 a,4) 14) 15) I v wherein R when taken alone, is hydroxy or a conventionalhydrolyzable ether or ester group convertible to a hydroxy group byhydrolysis, R when taken alone is hydrogen, and R and R4, when takentogether, are

0x0 or a conventional hydrolyzable ketal group convertible to an oxomoiety by hydrolysis; R is a primary alkyl group of from 1 to 5 carbonatoms; R; is hydrogen, lower primary alkyl, or lower acyl; R R11, R Rand R are each independently hydrogen or lower alkyl; Z is carbonyl or agroup of the formula R is hydrogen or lower acyl; R is hydrogen or loweraliphatic hydrocarbyl; T represents either. a single or a double bond; Urepresents a single or a double bond and is a single bond when T is asingle bond; m is an integer having a value of from 1 to 2; n is aninteger having a value of from 1 to 2; n is an integer having a value offrom 0 to 1 and is 0 when T represents a double bond and is 1 when Trepresents a single bond; r is an integer having a value of from 0 to land is 0 when T is a double bond and 1 when T is a single bond; and s isan integer having a value of from 0 to 1 and is 0 when U is a doublebond and 1 when. U is a single bond.

s' throughout the specification and appended aliphatic group'co'ntainingoolephinic' 'or acetylenicf unsaturation; the term alkylgroup denotes a saturated hydrocarbyl group, whether straight orbranched chain having 1 to 20 carbon atoms; the term primary alkyl groupdenotes an alkyl group having its valence bond from a carbon bonded toat least two hydrogens; the term acyl group denotes a group consistingof the residue of a hydrocarbyl monocarboxylic acid having 1 to 18carbon atoms formed by removal of the 'hydroxyl portion of the,carboxylgroup; the term oxyhydrocarbyl denotes a monovalent saturatedcyclic or acylic group consisting of carbon, hydrogen, and oxygencontaining only one oxygen in the form of an ether linkage; and the termlower, as applied to any of the foregoing groups, denotes a group havinga carbon skeleton containing up to and including eight carbons, such asmethyl, ethyl, butyl, tert.-butyl, hexyl, 2-cthylhexyl, vinyl, butenyl,hexenyl, ethynyl, ethylene, methylene, formyl, acetyl, 2-phenylethyl,benzoyl, methoxymethyl, l-methoxyethyl, and the like. The phraseologyconventional hydrolyzable ether or ester group convertible to a hydroxygroup by hydrolysis is meant to include ether groups such as loweralkoxy groups, e.g., methoxy, ethoxy, propoxy, t-butoxy (mostpreferable) and the like and lower oxyhydrocarbyloxy groups such astetrahydropyran-Z-yl-oxy, methoxymethyl-oxy, l-methoxy-ethyl-oxy and thelike; and'ester groups such as acyl groups, e.g., formyloxy, acetyloxy,propionyloxy, pivaloyloxy, undecenoyloxy, benzoyloxy and the like. Thephraseology conventional hydrolyzable ketal group convertible to an x0moiety by hydrolysis comprehends moieties of the formula -OR O-,ORS-,-OR N-- or 4M8- wherein R is alkylene having from 1 to 4 carbonatoms. Exemplary moieties are 1,2-ethylenedioxy, 2,2-dimethyl-1,3-propylenedioxy, 1,2-ethylenedimercapto, 2,3-butylenedioxy and thelike.

- In the formulas presented herein, the various substituents on cycliccompounds are joined to the cyclic nucleus by one of three notations, asolid line indicating a substituent which is in the [Si-orientation(i.e., above the plane of the paper), a dotted line indicating asubstituent which is in the (it-orientation (below the plane of thepaper), or a wavy line M) indicating a substituent which may be eitherthe aor fl-orientation. The position of R has been arbitrarily indicatedas the fi-orientation, although the products obtained in the examplesare all racemic compounds unless otherwise specified.

Preferred compounds are those wherein Y is n-alkyl, especially methyl,3,3-(alkylenedioxy)butyl wherein the alkylenedioxy group, when takenwith the 3-carbon of the butyl radical, forms a dioxolane ring system,especially ,3;( t ylene ylu y an -(233' butylenedioxy)- .butyl;, 3hydroxybutyl, 3 tert.-alkoxybutyl, especially 3- tert.-butoxybutyl, or 3(tetrahydfo-pyran-Z-yloxy) butyl; R is .n-alkyl, especially methyl andethyl; and, when s has a-value of 1, the 9a- (when m is 1) or 10a- (whenm 2) :hydrogen is transsoriented with respect to R .Subgeneric, to thetricyclic compounds of formula I are-the 3 substituted '6a,8-alkyll,2,3,5,6,6a,7,8-octahydrocyclopentafi][1]benzopyrans and the 3substituted-6afl-alkyl-l,2;5,6,6a,7,8,9-octahydro 3H naphtho-[2,1-:b]pyrans (by alternate nomenclature 3-substituted- 6afl-alkyl1,2,3,5,6,6a,8,9-octahydro 7H" naphthoclaims theterm hydrocarbylgroupdenotes a monoval 1 the formula: I

wherein R R R12, Z, Y and In areas defined above;

the 3 substituted 604,8 alkyl 1,2,3,5,6,6a ,7,'8,i9 ,9a-

-naphthol[2,l-b]pyrans, hereinafter referred to as monoenes, representedby the formula:

wherein R R R Z, Y, and m are as defined above;

wherein R R R R Z, Y and m are as defined above.

Alternatively, the tricyclic compounds of formula I can be classifiedaccording to the nature of Y, which determines the utility of thecompounds of this invention. The

first of these classes are the 3-alkyl compounds of the formula:

wherein R R R R Z, m, n, r, s, T and U are as de fined above and x is aninteger having a value of fromO to 6, inclusive.

These products are useful as intermediates for the synthesis of membersof a recently discovered class of 913,100;- or retrosteroids, and alsoare useful as intermediates for the synthesis of l0a-steroids, and othersteroidalmaterials.

' The second class of intermediates classified according to utilityarethe 3 (4-substituted'pentyl) compounds of the formula: V

(mon Ia wherein R1: R2 R R11: R12, R14 RIS! Z: T: and U are as definedabove; A is carbonyl or CR R and R and R are as defined above.

These compounds, which are useful as intermediates for the synthesis of19-nor-steroids of'the normal series, and other steroidal materials, canbe further classified as:

(1) The 3-(4-oxopentyl)-substituted cyclopentabenzopyrans andnaphthopyrans of the formula:

R5 CH2 fiCHCHCHg wherein R1: R2 R5, R11, R2712: R14 R15: Z: T: and

U are as defined above, 2 The 3 4,4 (ma) pentylj-lsubstitutedcyclopentabenzopyrans and naphthopyransof the formula:

formula:

c ash [M 7 3 U areas defined above and R is hydrogen,

lower acyl or lower oxyhydro carbyl. In compounds of formulale 4, R; ast-butyl is especially preferredr lower alkyl,

6 In a second aspect, this invention is concerned with a method forproducing the compounds of formula I via the following general reactionscheme:

YomoHbHdHoHiiioHaoHi YCHzMN R wherein Y, R R R R Z, and m are as definedabove; and B is hydrogen, lower alkyl or lower acyl.

Thus, the process of this invention comprises the general steps of (1)condensation of a 7-hydroxy-1-alken-3- one or a variant thereof (II), asdefined below, with a 2- alkylcycloalkane- 1,3 dione (III), as definedbelow, to produce diene (la); (2) saturation of the 9,9aor 10,1021-double bond of diene (Ia) to produce monoene (lb); and (3) introductionof a hydroxy, alkoxy, or acyloxy group at the 4a-position and a hydrogenatom at the 9bor 10bposition of monoene (Ib) to produce perhydrocompound (10). It is to be understood that the foregoing reactionsequence is merely schematic in nature, and that each depicted step canrepresent only one or more than one reaction, as will be more. fullydescribed herein.

It jwill be noted "that the diene, monoene'and perhydro compounds ofthis invention can bear a'3-(4-oXopentyD- f substituent, When such aside chain is desired, it is how" ever preferable to perform thereactionsequence with compounds, having the'oxo moiety of the '4-oxopentyl sidechain in protected form. Protection can beeifecte'd by ketalization (toform lower alkylenedioxy or other hetero variants thereof), or byreduction to a hydroxy moiety 7hydroxy-1-dodecen-3-one, 7acetoxy-1-nonen3-one, 7-'

benzoyloxy-1-nonen-3-one, 7-methoxy-lsnonen-3-one,'. 7-.

benzyloxy-l-nonen-B-one, 11,1 1-ethylenedioxy-7-hydroxy-1-dodecen-3-one, 7,11-dihydroxy-1-dodecen 3 one, 1'1-tert.-butoxy-7-hydr0xy-l-dodecen-S-one, 11(tetrahydropyran-Z-yloxy)-7-hydroxy-l-dodecen-B-one, and the like.

The 7-hydroxyalken-3-ones of formula II above are readily synthesizedfrom (A) a glutaric acid anhydride, (B) a 2-alkylcyclohexane-1,3-dione,(C) a glutaraldehyde or (D) a butyrolactone, as is illustrated by thefollowing sequences leading to 7-hydroxynonen-3-ones:

O 0 011 1 GHtilHCILH? O-alkyl 0 0 11011 1 CHCHOHz O-alkyl n RCH Insequence A, a six-membered ring cyclic anhydride such asglutaricanhydride is reacted with a lower alkanol, for example, ethanol,to produce a monoalkyl glutarate half-ester. This half-ester is reactedwith thionyl chloride to produce the corresponding acid chloride, whichin turn is reacted with a dialkyl cadmium compound o oiiiorronomolycmouono mom znolkon,

on i o Yomhnononomiiorbom tanoic acid which, on-hydrogenation in thepresence of sodium hydroxide and Raney nickel followed by acidification,yields 5-substituted-S-valerolactone.

Sequence C involves reacting a 1,5-alkylenedial such as glutaraldehydewith a" Grignard reagent of the formula Ycn -M x, a wherein Y is asdefined above and X is bromine'or chlorine to form a6-substituted-tetrahydfopyran-Z-ol. This reaction and the productsobtained thereby are ffdescribed in greater detail in US. patentapplication of David A. Andrews and Gabriel Saucy, Ser. No. 633,693,filed Apr; 26; 1967, entitled 6-Sub stituted Tetrahydropyran-2-Ols andProcess for Their Production. Sequence D comprises reacting, forexample,*butyrolactone with thionyl chloride in the presence of zincchloride to produce a 4 -chlorobutyric acid chloride. The acid chlorideis reacted with the dialkylcompound.

as defined above to produce S-substituted-l-chloropentan- 4one. Thechloroketone, in the form of its ketal, for example, the ethylenedioxyketal, is reacted with magnesium to form 4-(ethylenedioxy)-5-substituted pentyl magnesium chloride. This Grignard reagent isreacted with acrolein to yield, upon hydrolysis,8-substituted-3-hydroxyocten-7- one. This hydroxy ketone is reduced to7-substituted-1- heptene-3,7-diol by reaction with lithium aluminumhydride, and the diol converted to 7- substituted-7-hydroxyhepten-3-oneby reaction with manganese dioxide.

Because of the susceptibility of the vinyl group of the7-hydroxy-1-alken-3-one to oxidation, it is desirable, although notessential, that this compound be converted to more stable variants, suchas those of the formula:

wherein R R Y and Bare as defined above; and

R is chloro, hydroxy, lower alkoxy, lower hydrocarbylamino or di(lowerhydrocar-byDamino.

Variants of formula IIa and methods for their preparation are describedin detail in my US. patent application Ser. No. 604,124, filed Dec. 23,1966, entitled a-Olefins.

As exemplary, these compounds of formula Ha are readily produced fromthe vinyl ketones of formula II by known techniques. For example,1-chloro-7-hydroxyalkan-3-ones areobtained, by the anti-Markownikoffreaction of the vinyl compound with hydrogen chloride in known manner.l-hydroxy and l-alkoxy derivatives are obtained by the base-catalyzedreaction of water or a lower ,alkanol, for example, methanol, with thevinyl ketone. Additional derivatives are formed by the reaction of thevinyl ketone with a mono (lower hydrocarbyl) or di(lowerhydrocarbyl)-amine to form the Mannich base l-(lower hydrocarbyl)aminoor1-di(lowerv hydrocarbyl)amino-7- hydroxyalkan-3-one. A particularlyadvantageous procedure is to oxidize a hydroxy vinyl compound of formulaIVa with manganese dioxide in the presence of such an amine. In someinstances, particularly in large scale commercial operation, it may bedesirable to convert the Mannich base to its crystalline acid additionsalts, particularly quaternary ammonium salts. All of the chloro,hydroxy, alkoxy, and aminoalkanones yield the alkenones of formula 11under the conditions of the condensation with the2-alkylcycloalkane-1,3-dione. p

The compounds of formula II can be used in the form of still anothervariant. This is the cyclized variant comprising a cyclic hemiketal,i.e., 2-tetrahydropyranol of the formula:

YCH -wR1 R12 IIb wherein Y is as defined above and R is lowerhydrocarylamino or di(lower hydrocarbyl)amino.

The variants of formula 11b can be prepared from compounds of formula IIby reaction with the same reactants as are used to produce thosecompounds of formula IIa wherein R is lower hydrocarbylamino or di(lowerhydrocarbyl) amino. As is apparent, those compounds of formula Hawherein R has the aforesaid meanings and the compounds of formula III)are isomers. These isomers exist in the form of a ketone of formula Haor in the form of the cyclic hemiketal of formula IIb or as anequilibrium mixture of the two forms. Whether a particular 'Mannich baseof formula IIa exists in that form or the hemiketal form on in anequilibrium mixture consisting primarily of one or the other will dependupon the environmental condtitions in which it is placed, such astemperature, solvent and pH of reaction medium, as well as theparticular meaning of Y and R or R Either form is useful for thepurposes of this invention since these isomers are used in reaction withcompounds of formula III, infra, andeither the acyclic form of formulaIIa or the cyclic hemiketal form of formula Hb is useful for thispurpose. A particular advantage of the cyclic form is its greaterstability as compared with the acyclic form and also ascompared with thevinyl ketones of formula II. In order to obtain the cyclic form it isessential that in the compound of formula IIa, B is hydrogen. Acidicconditions shift the equilibrium away from the cyclic form. Use of anoptically active amine, e.g., phenylethylamine, offers the advantage ofresolving the compound, for example, via salt formation, to give anoptically pureisomer of formula IIa or IIb which is then used in theremainder of the reaction sequence of this invention and when coupledwith the unique asymmetric induction and preservation of opticalspecificity thereof olfers a facile route to optically pure steroidalmaterials.

In a further aspect of this invention optically active compounds offormula IIb where Y is 3-oxobutyl are prepared frorn optically activeprecursors according to the following reaction sequence:

JDiII II-b-I.

Where R is lower alkyl; and R R and R are as above.

As indicated an optically active 9-oxo-decanoic acid fi-lactone offormula XXI is treated with a lower alkoxy amine or an acid additionsalt thereof, e.g., a mineral acid salt such as the hydrochloride,hydrogen sulfate, hydrobromide and the like to form the correspondinglower alkoxy, imino compound XXII. A preferred lower alkoxyamine forthis purpose is methoxyamine, most preferably in the form of itshydrochloride salt. This reaction is conducted at a temperature in therange of from about -10 to 50 C., most preferably in the range of fromabout 25 to 30 C. A solvent may be employed to facilitate the course ofthe reaction. Preferred solvents include organic nitrogen bases such asfor example, pyridine, triethylamine, dimethylamine, trimethylamine andthe like. After completion of the reaction wherein a mineral acid saltof the lower alkoxyamine is employed it is desirable to add a basicorganic amine to the reaction mixture to neutralize the acid produced.Suitable basic organic amines for this purpose include the tertiaryamines, e.g., trialkylamines such as triethylamine.

In the second step of this sequence the keto lactone XXII is treatedfirst with vinyl Grignard, e.g., vinyl magnesium bromide or chloride inan ethereal solvent, e.g.,

.tetrahydrofuran at a temperature in the range of from XXIII where R Rand R are as above where R R R and R are as above.

The intermediate oxime compound XXIV when treated with dilute aqueousacid, such as aqueous mineral acid, e.g., 2 N sulfuric acid ishydrolyzed to the ketone with concomitant purification of the amine toyield the desired compound of formula IIb-l. This acid treatment step isconveniently carried out in the presence of a suitable inert organicsolvent, preferably a ketonic solvent such as acetone, at a temperaturein the range of from about to 50 0., preferably in the range of fromabout 20 to 30 C., e.g., 25 C.

It should be noted that intermediate compounds XXIII and XXIV need notbe isolated or otherwise purified during the aforesaid transformationsbut can be utilized in crude form for further steps.

The optically active 9-oxo-decanoic acid 61actone of the indicatedconfiguration may be prepared from racemic 5,9-dioxodecanoic acid bymicrobiological reduction followed by lactonization. This procedure,which is not part of the present invention, is described in detail inUS. Pat. No. 3,657,070, Microbiological Preparation of Optically Active9-Oxo-5(S)-Hydroxy-Decanoic Acid and the Lactone Thereof, inventorsJulius Berger and Michael Rosenberger.

As is indicated above, the 7-hydroxy group of the 7- hydroxyalkanone offormula II or IIa can be esterified or etherified for the condensationreaction with the cycloalkanedione. These reactions can be effected inknown manner. For example, the 7-hydroxyalkan-3-one can be reacted witha carboxylic acid or an acid chloride to produce an ester, or can beconverted to an ether by either (1) preferably, known acid catalyzedetherifications, e.g., with isobutylene or dihydropyran or (2)conversion of the 7-hydroxyalken-3-one to its sodium salt followed byreaction of the salt with an alkyl halide. In the event R is hydrogen,this hydroxyl group is also etherified or esterified.

The starting material of formula H or variant thereof can either be usedin racemic form or in optically active form. When used in opticallyactive form, the 7S-antipode is preferred for reasons more fullyexplained below.

The second reactant employed in the condensation as generally mentionedabove is a 2-(lower alkyl)cycloalkane-1,3-dione of the formula:

wherein R and m are as defined above.

These compounds are known compounds and description of their synthesisis accordingly unnecessary. Suitable compounds include2-methylcyclopentane-1,3-dione, 2-ethylcyclop'entane-l,3-dione,2-propylcyclopentane-1,3-dione, 2- butylcyclopentane-1,3-dione, 2methylcyclohexane-l,3- dione, and the like. a

The conditions for the condensation of ketone (II) or variant (Ila, IIbor IIb-l) with cyclic dione (HI) are not narrowly critical, although itis preferred, particularly when the acyclic ketone is charged as thevinyl ketone,

III

that a non-oxidizing atmosphere, e.g., nitrogen or argon, be employed.It is further preferred that an antioxidant, for example, phenoliccompounds such as hyd-roquinone, be present. Furthermore, the reactioncan be conducted in the absence or presence of acid or base promoters.Suitable basic promoters include those heretofore known to promote theMichael condensation, including inorganic bases, for example, alkalimetal hydroxides, such as sodium hydroxide or potassium hydroxide, andorganic bases, including alkali metal alkoxides, for example, sodium orpotassium methoxide or ethoxide, and ammonium hydroxides, particularlybenzyltrialkylammonium hydroxide. A preferred class of base promotersare the amines, especially tertiary amines and most preferablypyridine-type compounds such as pyridine and the picolines. Acidpromoters which can be employed include organic carboxylic acids such asacetic acid or benzoic acid; organic sulfonic acids such asp-toluenesulfonic acid; and mineral acids such as sulfuric acid,phosphoric acid, hy drochloric acid, and the like. The amount ofpromoter employed is not narrowly critical and can vary from catalyticamounts to molar amounts.

The ratio of ketone (II) or variant (IIa, Ilb or IIb-l) to cyclic dione(III) is not narrowly critical, although approximately equimolar amountsare preferred. Although there is no particular advantage to the use ofexcesses of either reactant, the cycloalkanedione can be more readilyemployed in excess because, due to its general low solubility in knownorganic solvents, unreacted cycloalkanedione can be easily recoveredfrom the reaction mixture.

The reaction temperature is not critical and can vary from roomtemperature or below to reflux temperature or higher. The condensationis preferably conducted in the presence of an inert solvent to insure afluid reaction mixture and uniform reaction temperatures. Primaryalcohols are not desirable due to their tendency to react with vinylketones. Suitable solvents include tertiary alcohols such astert.-butanol; aliphatic and aromatic hydrocarbons such as cyclohexane,hexane, octane, benzene, xylene, toluene, and the like; ethers such asdiethyl ether, tetrahydrofuran, and the like; chlorinated hydrocarbonssuch as carbon tetrachloride, chloroform, and the like; as well asdipolar aprotic solvents such as dimethylsulfoxide and the N,N-disubstituted amides such as dimethylformamide or dimethylacetamide.

The product of the condensation, depending upon the nature of vinylketone or variant (II, Ila, III) or IIb-1) and/or the reaction promoteremployed, can be one or more of the compounds having the formulae:

wherein R R R B, Y, and m are as defined above.

When vinyl ketone (III is a 7-alkoxyor 7-acyloxy compound, the productwill be a compound of formula IV. However, when the vinyl ketone is a7-hydroxy compound, or the reaction conditions are sufficient to converta 7-alkoxyor 7-acyloxy group, if present, the product will depend uponthe promoter.

When the promoter is an acid or a relatively weak base, such aspyridine, or when no promoter is employed at all, the reaction productobtained from the 7-hydroxy vinyl ketone is the diene, i.e., tricyclicenol ether (Ia-1). When a strong base, such as sodium or potassiumhydroxide, is employed as a promoter, a crystalline product having theformula VI is isolated, although compounds of formulae IV and V are alsopresent in the reaction mixture. However, the compounds of formulae IV,V, and VI, upon treatment with an acid, such as acetic acid,para-toluenesulfonic acid, or'sulfuric acid, readily form the diene,i.e., tricyclic enol ether (Ia-1). It should also be noted that theconversion of the acyloxy or alkoxy groups of compound (IV) to a hydroxygroup in an acidic medium is accompanied by cyclization to enol ether(Ia-1).

The condensation of a vinyl ketone of formula II or a variant thereof offormula 11a or IIb with a cycloalkanedione of formula IIIis one of thekey features of this reaction. It'is in this condensation that specificstereochemical induction at onemember of the critical C/D-ring junctionof the eventual steroidal product occurs. Thus, this invention isparticularly-advantageous in that it involves a unique asymmetricinduction. Thus, the products of the condensation, i.e., the dienones offormula Ia-l, have at least two asymmetric centers at positions 3 and 6apermitting theoretically of two racemates or four optical antipodes.However, as a result of the condensation of this invention, when using aracemic starting material of formulas II, Ila or IIb wherein R 11 and Rare both hydrogen only a single'racemate of formula Ia-l results andwhen using an optically active starting material of formulas II, IIa,IIb orIIb-l wherein R and R are both hydrogen only a single opticalantipode of formula Ia-l results. It has further been found that whenstarting with a compound of formula II or IIa with a7S-stereoconfigurationor of formula 'IIb with correspondingstereoconfiguration there is obtained the more desirable opticalantipode of formulaIa-l having a 6ap-stereconfiguration. Thus, toprepare steroidal materials having the more desired 133-stereoconfiguration' by the synthesis of this invention one can eitherstart with the antipode of formula H, 11a, III) or IIb-l, which can bepreparedbyresolving a racemic compound e f-formula II, He. or IIb, orone can resolve at some intermediate stage subsequent to thecondensation with a cycloalaknedione of formula III or one can resolvethe end-product steroidal material. In any event, the unique asymmetricinduction concurrent to the condensation of this invention renders theobtention of a single optical antipode as" an end-product more facile.The simultaneous formation of the dienol ether of formula Ia-l withunique asymmetric inductionis a special advantage of thisinvention.

J The dienes of formula Ia in the presence of water and acid, e.g.,sulfuric acidin acetone, aqueous acetic acid or aqueous hydrochloricacid in dioxane, undergo acid hydrolysis to form indenones of theformula The indenones of formula Ia are themselves convertible tocompounds of formula Ia via dehydration, for example, via acid catalyzedazeotropic distillation in benzene. Suitable acid catalysts arep-toluenesulfonic acid, potassium bisulfate, boron trifluoride etherateand the like. This reversible hydrolysis of compounds of formula Ia isuseful in their preparation and purification. Thus, in instances wherethe direct purification of compounds of formula Ia is difficult it isoften more facile to hydrolyze the compound of formula Ia to a compoundof formula Ia, which can then be purified, for example, bychromatography, and subsequently be reconverted to the desired compoundof formula Ia via dehydration.

The ketodienes of formula Ia-l are readily converted to thecorresponding 7fi-alcohols and their esters as represented by theformula:

wherein Y, R R R R and m are as previously defined,

by the sequence of reactions comprising reduction of the ketone to thealcohol and, if desired, subsequent esterification.

The reduction can be effected by any of the known methods for thechemical reduction of a ketone, e.g., by reaction of dienone (Ia-l) withan alkali metal or Group III-metal reducing agent. By the term alkalimetal, as employed herein, is meant a Group I-metal having an atomicnumber of from 3 to 19, inclusive, i.e., lithium, sodium, and potassium.Group III-metals include those having atomic numbers of from 5 to 13,inclusive, i.e., boron and aluminum. Illustrative examples of thesereducing agents include an alkali metal, preferably lithium or sodium,in liquid ammonia or a liquid aliphatic amine; tri(loweralkoxy)-aluminum compounds such as triisopropoxyalurninum; di(loweralkyl)-aluminum hydrides such as diethylaluminum hydridediisobutyl-alu-minum hydride; alkali metal-Group III-metal complexhydrides such as lithium aluminum hydride, sodium aluminum hydride, andsodium borohydride; tri(lower alkoxy) alkali metal- Group III-metalcomplex hydrides such as trimethoxy lithium aluminum hydride andtributoxy lithium'alumin'um hydride; diisobutylaluminum hydride and thelike. The alkali metal-Group IH-metal complex hydrides are pre-, ferredas reducing agents, with the nonalkaline reagents, such as lithiumaluminum hydride, being especially preferred.

This reaction is effected in any suitableinert reaction medium, such ashydrocarbons, e.g.,lcyclohexane, benzene, toluene, and xylene; ethers,e.g., diethyl ether, diisopropyl ether, and tetrahydrofuran. .Proticsolvents, such as water 1 or alcohols, should not be employed whenlithium aluminum hydride is the reducing agent, but can be employed withsodium borohydride.

The remaining reaction conditions are not narrowly critical, although itis generally preferred to effect the reduction at reduced temperatures,i.e., below about room temperature (about 20-25 C.). Temperatures in therange of from about 0 C. to about room temperature are normallyemployed.

In the reduction of a dienone of formula Ia-1 to a dienol of formulaIa-2 any keto group in the side chain symbolized by Y is simultaneouslyreduced and any acyloxy group is hydrolyzed, in both cases yielding acorresponding hydroxy group. Any such side chain hydroxy group can beconverted to an oxo moiety by treatment with conventional oxidizingmeans such as manganese dioxide. It is, however, preferable to usestarting materials with etherified hydroxy moieties or ketalized oxomoieties in the side chain since these are unaffected by the reduction.

The free alcohol is recovered from the reaction mixture after treatmentof the mixture with acid. The alcohol can be esterified in known manner,for example, by base-catalyzed reaction with a carboxylic acid halide orcarboxylic acid anhydride. Illustrative bases include inorganic basessuch as sodium hydroxide and potassium hydroxide and organic bases suchas a sodium alkoxide or an amine, especially a tertiary amine, and moreparticularly, pyridine and the picolines. I

The ketodienes of formula la-l can also be converted to their7fl-hydroxy-7-ot-hydrocarbyl derivatives represented by the formula:

wherein Y, R R R R and m are as previously defined and R is lowerhydrocarbyl by reaction of the ketodiene with a Grignard reagent of theformula:

This Grignard reaction is conducted in known manner. For example, theGrignard reagent is prepared by reacting a hydrocarbyl halide withmagnesium in an ether reaction medium, for example, ethyl ether ortetrahydrofuran, at elevated temperature, generally in the range of fromabout 40 C. to about 75 C. The ketodiene (Ia-1) is then added to theGrignard solution at about room temperature, although higher or lowertemperatures can be employed. The resulting reaction product ishydrolyzed to produce the free alcohol, which can be esterified asdiscussed above.

Alternatively, the alcohols can be prepared by reaction of ketodiene(Ia-l) with a hydrocarbyl alkali metal compound such as methyl lithium,sodium acetylide, potassium acetylide, and the like.

If a dienone of formula Ia-l is to be converted to a diene of formulaIa-3 then a starting material of formula Ia-l wherein the side chain Yincludes an oxo group should not be used. Also, during the course ofsuch conversion any ester moieties present in the side chain will behydrolyzed.

Illustrative examples of the dienes represented by formulae Ia-2 andIa-3 include 3,6afl-dimethyl-75-hydrovy-1 ,2,3 ,5,6,6a,7,8-octahydrocyclopenta[f] 1]benzopyran;

3,6aB-diethyl-7p-hydroxy-l,2,3,5,6,6a,7,8-octahydrocyclop enta [f] lbenzopyran;

3 -ethyl-6afl-methyl-7B-acetoxy-1,2,3,5,6,6a,7,8-octahydrocyclopenta [f]1] benzopyran 3-ethyl-6a;3-methyl-7;8-benzoyloxy-l,2,3,5,6,6a,7,8-

octahydro cyclopenta [f l ]benzopyran;

3-ethyl-6a/3-dimethyl-7B-hydroxy-1,2,3,S,6,6a,7,8-octahydro-cyclopenta[f 1 1 -b enzopyran;

3 ,7a-diethy1-6afi-methyl-7B-hydroxy-1,2,3,5,6,6a,7,8-octahydrocyclopenta [f] 1 ]benzopyran;

3 -ethyl-7/8-hydroxy-6aB-methyl-7a-vinyl-1,2,3 ,5 ,6,6a,7,8-

octahydro-cyclopenta[f] 1 benzopyran;

3 -ethyl-7aethylnyl-7fl-hydroxy-6a 3 methyl- 1,2,3 ,5 ,6,6a,

7,8-octahydrocyclopenta[f] [1]benzopyran;

7 ,B-acetoxy-B-ethyl-6ap7wdimethyl-1,2,3,5,6,6a,7,8-

octahydro cyclopenta [f] 1 ]benzopyran;

3-ethyl-7B-hydroxy-6a,B-dimethyl-1,2,3 5 ,6,6a,8,9-

octahydro-7H-naphtho[2,1-b1pyran;

7fl-hydroxy-6afi-methyl-3- 4-oxopentyl) -1 ,2,3,4,5 ,5 a,7,8-

octahydrocyclopenta[f] 1 benzopyran;

6afl-ethyl-7B-hydroxy-3- (4-oxopentyl )-1,2,3,5,6,6a,7,8-

octahydrocyclopenta[f] [l]benzopyran;

3 (4,4-ethy1enedioxy) pentyl] -7/3-hydroxy-6a,B-methyl-1,2,3,5,6,6a,7,8-octahydrocyclopenta [f] [1]benzopyran;

3 [4,4- 2',3 -butylenedioxy-p entyl]-6a;3-ethyl-7p-hydroxy-1,2,3,5,6,6a,7,8 octahydrocyclopenta [f] [1]benzopyran;

3 (4-t-butoxypentyl) -7fl-hydroxy-6aB-methyl-1,2,3,5,6,6a,

7,8-octahydrocyclopenta [f l ]benzopyran;

3 -(4-t-butoxypentyl) -6aB-ethyl-7B-hydroxy-1,2,3 ,5 ,6,6 a,7,

8-octahydrocyclopenta[f] [1]be nzopyran;

7,8-hydroxy-3- 4-hydroxypentyl -6a;8-methyl- 1,2,3 ,5 ,6,6a,

7,8-octahydrocyclopenta[f] 1]benzopyran and the like. p

The second step of the generalsynthesis of the tricyclic compounds ofthis invention comprises conversion .of the dienes of formula Ia to themonoenes of formula Ib. by catalytic hydrogenation. Suitable catalystsinclude the noble metals such as platinum, palladium, rhodium, and thelike, as well as Raney nickel and other hydrogenation catalysts. Thesecatalysts can be employed in the form of the metal alone, or can bedeposited on suitable support materials, such as carbon, alumina,calcium carbonate, barium sulfate, and the like. Palladium and rhodiumare preferred as catalysts. The hydrogenation is preferably conducted inthe presence of inert solvents such as hydrocarbons, alcohols, ethers,and the like. The reaction conditions of pressure and temperature arenot narrowly criti cal, and normally a hydrogen pressure of about oneatmosphere and a temperature of about room temperature are employed.These ambient conditions are generally preferred to avoid significanthydrogenation of the 4a,9b (10b)-double bond, although more severeconditions, for example, up to about C. and up to about 100 atmospheres,can be employed if desired. The hydrogenation medium can be acidic,neutral, or basic, as may be desired, although neutral media, such ashydrocarbons, e.g., toluene or hexane, or basic media, such as analcohol-base, e.g., methanol-sodium hydroxide, mixture are preferred forbest results. In general, hydrogenation of the diene of formula Ia leadsto the corresponding monoene of formula Ib. However, in the event R isan unsaturated hydrocarbyl radical, the hydrogenation, in addition tohydrogenatirig the ring double bond, also hydrogenates thela-hydrocarbyl substituent, converting it to an alkyl group.

Via the aforesaid catalytichydrogenation C/D-trans compounds are formedin a major proportion when hydrogenating a diene of formula I a-2. Thismethod thus provides an advantageous synthesis of C/D-trans steroidalmaterials. When hydrogenating a diene of formula Ia-l, C/D-cis compoundsare formed -in a majorproportion.

k... I L1 wherein Y, R R R and mare as previously defined,

can be converted to the corresponding alcohols or esters of the formula:V I

YCHINW NwRu or to the 7fi-hydroxy-7a-hydrocarbyl compounds of theformula:

wherein Y, R R R R R 3 and m are as previously defined, i

by the techniques discussed above regarding the dienes of formula Ia.

When Z is carbonyl and the hydrogenation is effected under basicconditions, there is a tendency toward the production of predominantlythe 6a/9a(10a) cis compound; that is, the hydrogen atom in the 9a(l0a)-position of formula Ib-l is predominantly in the p-orientation.When these compounds are intended as intermediates for the synthesis ofsteroids having the C/D-trans-orientation, this technique is notparticularly desirable. Although the ratio of ,8- to a-orientation fallsto about 1:1 at neutral conditions when hydrogenating a compound whereinZ is carbonyl, it is preferred to hydrogenate a 7B-alcohol or ester offormula Ia-2 because the products of this hydrogenation arepredominantly the 6a/9a(10a) -trans compounds. Compounds of formula Ia-3when subjected to the hydrogenation yield a ratio of ,8- totat-orientation in between that ofthe compounds of formula Ia-l and thatof the compounds of formula Ia-2. When monoenes of formula Ib-l havingC/D-trans configuration are desired, it is preferable to first reducethe dienone of formula Ia-l to a corresponding hydroxy compound offormula Ia-2 prior to the catalytic hydrogenation. Following thecatalytic hydrogenation the carbonyl moiety in formula Ib-l can beregenerated by conventional means, such as oxidation with chromiumtrioXide.

The monoene compounds of formula Ib prepared by theabove-describedhydrogenation contain at least three 18 asymmetric centers, at positions3, 6a and 9a when m is one and at positions 3, 6a and 10a when m is two.With respect to these three centers there are thus eight antipodalconfigurations possible. By virtue of the unique asymmetric induction ofthis invention, proceeding from a racemic starting materialof formulaII, Ila or IIb only four of these antipodes of formula Ib are preparedand proceeding from an optically active starting material of formula II,IIa, lb or IIb-l only two of these antipodes of formula Ib are prepared.Moreover, by the abovedescribed hydrogenation of this invention and byappropriate selection of the 7-substituent in the diene of formula Iasubjected to the hydrogenation there can pre dominantly be prepared thedesired 6a,9a(10a) transstereo-configuration. Thus, the eventualobtention of the more desired 13p-C/D-trans-configuration in theultimate steroidal products is rendered more facile by thestereoselective reactions provided by this invention.

Illustrative examples of the monoenes of formula Ib include 3,6a8-dimethyl-1 ,2,3,5,6,'6a,9,9a-octahydrocyclopenta[f] 1 -benzopyran-7'(8H) -one;

3,6afi-diethyl-1,2,3,5,6,6a,9,9a-octahydrocyclopenta[f]- 1 -benzopyran-7 (8H -one;3,Gafl-dipropyl-1,2,3,5,6,6a,9,9a-octahydrocyclopenta[f] 1]benzopyran-78H) -one;3,6aB-dimethyl-7B-hydroxy-1,2,3,5,6,6a,7,8,9,9a-decahydrocyclopenta [f1] -benzopyran; 7fl-acetoxy-3,-6a8-dimethyl-1,2,3,5,6,6a,7,8,9,9a-decahydrocyclopenta [f] 1 ]benzopyran;7,8-hydroxy-3, 6a13,7oc-trimethyl-1,2,3,5,6,6a,7,8,9,9a-

decahydrocyclopenta [f] 1 benzopyran;3,6aflJa-triethyl-7B-hydroxy-l,2,3,5,6,6a,7,8,9,9a-decahydrocyclopenta[f]1 ]benzopyran; 3,6afl-dimthyl-1,2,3,5,6,6a,8,9,10,10a-decahydro-7H-naphtho- [2, l-b] pyran-7-one;6ap-methyl-3-(4-oxopentyl)-1,2,3,5,6,6a,9,9a-octahydrocyclopenta [f1]benzopyran-7 8H) -one; 6a;8-ethy1-3-(4-oxopentyl)-1,2,3,5,6,6a,9,9a-octahydrocyclopenta [f] 1 -benzopyran-7 8H -one;

3-[ (4,4-ethylenedioxy) pentyl] -6afi-methyl- 1,2,3 ,5,6,6a,9,9a-octahydrocyclopenta [f] 1 benzopyran-7 8H) one;

3- (4-t-butoxypentyl -6aB-methyl-1,2,3,5,6,6a,9,9a-octahydro cyclopenta[f 1 1 benzopyran-7 8H -one 3- (4-hydroxypentyl-6afl-methyl-1,2,3,S,6,6a,9,9a-octahydrocyclopenta [f] l]-benzopyran-7(8H) -one;

3- (4-hydroxypentyl) -6a/8-methyl-1,2,3,5,6,6a,7,8,9,9a-

decahydrocyclopenta [f] 1]-benzopyran-7-ol,

6afl-ethyl-3-(4-hydroxypentyl)-1,2,3,5,6,'6a,7,8,9,9a-decahydro cyclopenta [f 1 -b enzopyran-7-ol and the like.

The final reaction of applicants general process for the compounds ofthis invention is the conversion of the monoene of formula Ib to theperhydro compound of formula Ic by reaction of the monoene with acompound having the formula: I

' R OH wherein R is as previously defined.

That is, the monoene of formula Ib is reacted with water, a primaryalcohol, or a carboxylic acid. This reaction is catalyzed by mineral ororganic acids, for example, hy

miscible with water and a solvent for the monoene of for mula Ib.Solvents of this nature include acetone, ten.- butanol, dioxane, and thelike. The reaction temperature vnr is not critical, and ambienttemperature is normally employed, although higher and lower temperaturescould be employed if desired. a

In addition to the addition of the R OH compound,

this step effects the conversion o'f'a ketalized side chain 5 Y CH2-wherein Y, R R R R and m are as previously defined,

are readily converted to their corresponding alcohols:

Rn Ic-2 wherein Y, R R R R R and m are as previously defined,

I I I I I l H YCH; AMIQMN R1 wherein Y, R R R R R R and m are aspreviously defined,

by the previously described methods.

In a modification of the general technique outlined above, one cansimultaneously effect the hydrogenation and hydration steps, forexample, by hydrogenation of a diene of formula Ia in aqueous sulfuricacid. When this simultaneous hydrogenation-hydration reaction iseffected, it is preferred to begin with a diene having a hydroxyl groupin the Iii-position.

Illustrative examples of the compounds falling within the scope offormula Ic include 4a-hydroxy-3,dafi dimethyl peihydrocyclopenta [f] 1]I benzopyran-7-one; 4a acetoxy-3,621 8-dimethyl perhydrocyclopenta[f][=1] benzopyran-7-one; 4a-metho'xy-3,6afl-dimethyl-perhydrocyclopenta[f] 1 b1'1zopyr'an-7-one;3,Gafi-diethyl-4a-hydroxyperhydro-cyclopenta [f] [1] benzopyran-7-on'e;3-[4,4- (2',3") -butylenedioxy-pentyl] -6ap-ethyl-4ahydroxyperhydro'cyclopenta [f 1]ben zopyran-7-one;4a,-7B-dihydroxy-3,6a/8-dimethylperhydrocyclopenta- [f] [1 benzopyran;

" penta[f][l]benzopyran; e v I 4a,7pdi acetoxy) -3,6a13-dimethyl-perhydrocyclopenta- [f] [l]benzopyran;

4a,7 3-di(acetoxy) -3,6afi-dimethyl-perhydronaphtho ]py a4a-hydroxy-6aB-methyl-3- (4-oxopentyl) -p erhydrocyclopenta [f] lJ-benzopyran-lone;

3-[ (4,4-ethylenedioxy -pentyl]-4a-hydroxy-6afl-methylperhydrocyclopenta [f] [l]benz opyran-7-one;

3- (4-t-butoxyp entyl) -4a-hydroxy-6aBmethyl-perhydrocyclopenta [f lbenzopyran-7-one;

4a-hydroxy-3- (4-hydroxypentyl -6a;8-methyl-perhydr'ocyclopenta [f 1benzopyran-7-one;

3- (4-hydroxypentyl -6aB-methy1-perhydrocyclopenta- [fl]benzopyran-4a,7-diol;

3-(4-hydroxypentyl) -6a 8-ethyl-perhydrocyclopenta- [f][1]benzopyran-'4a,7-diol; r

6aB-methyl-3- (4-oxopentyl -perhydrocyclopenta[ f]' [21]benzopyran-4a,7-diol;

. and the like.

Although in the various compounds of formula I, as well as theirprecursors of formulas II, 11a and 11b, the symbol Y comprehends a3-oxobutyl moiety, it should be noted that it is not preferred to workdirectly with such oxo-substituted compounds. This is because in many ofthe reaction steps utilized herein such an oxo moiety would itself beaffected. Accordingly, it is preferred to protect such an oxo moiety andregenerate the 0x0 moiety from its protected form at any desirable stageof the reaction sequence. Protection of the 0x0 moiety can be effectedaccording to means known per se. Similarly, regeneration of the 0x0moiety from its protected form can be effected by means known per se.Thus, one preferred method of effecting protection of the oxo moiety isto convert it to its ketal by reaction with an alkanediol in a knownmanner. Advantageous results are obtained where protection of the oxomoiety is effected at an early stage in the synthesis. An especiallypreferred alkanediol is butanediol which affords excellent resistance toattack by nucleophilic reagents. When butanediol is employed, R and Rwhen taken together are for example, 2,3-butylenedioxy. Similarly, anoxo moiety can be converted to its dithia ketal by reaction withdithioethane in a known manner, for example, in acetic acid at roomtemperature and in the presence of boron trifluoride. Moreover, a mono-.

thia ketal can similarly be prepared in a known manner,

aza ketals can be prepared in a known manner, for-example, by reactionof the 0x0 moiety with 2-hydroxyethylamine in the presence of acid.Finally, the 0X0 moietycan' be reduced to the corresponding hydroxycompound which can then be etherified or esterified. As indicated above,

the 0x0 moiety can be regenerated from its protected forr'n at anydesired stage of the reaction sequence. Thus, itcan be readily producedby hydrolysis of the alkylene'-- dioxy ketals in a known manner.Similarly, it can be regenerated from the dithia ketal in a knownmanner, for

.example, by treatment'with phenylme'rcuric chloride and calciumcarbonate in ethanol or by treatment with'dioxane in methanolichydrochloride. Also, it can be regen erated from a monothia ketal in aknown manner, for ex ample, by treatment under strong acidic conditions,for I example, by treatment with aqueous'sulfuric-acid'in diox'ane orhydrochloride in acetic acid. Moreovenit can be regenerated from amonoaza ketal in a known manner, for

example, by treatment with a strong aqueous acid Also," ethers and/0resters can be reconverted to "the free can beoxidiz'e'd tol give' theexp i moiety.

As indicated above, the tricycliccornpounds of this in} vention areuseful as intermediates for the preparationo'f various steroidcompounds, depending upon the nature of 21 Y. For example, compoundswherein Y is hydrogen or alkyl lead to 913,10oL-Sl6f0id5 or10a-steroids, whereas compounds wherein Y is 3-substituted-butyl, leadto 19-n0rsteroids of the normal series, as illustrated by the followingreaction scheme.

where R is hydrogen or alkyl; R is lower alkyl and the remaining symbolsare as above.

In the first step of this reaction scheme, the compound of formula 10 isoxidized to form bicyclic compound of the formula X wherein Y ishydrogen, alkyl, 3-ketalbutyl, or etherified 3-hydroxybutyl, by contactwith such oxidizing agents as chromic acid, potassium dichromate, orpotassium permanganate. Jones reagent (chromic acid, sulfuric acid andacetone), or a chromic acid-acetic acid mixture are preferred asoxidizing agents. The nature of Z is unchanged in this reaction, exceptwhen Z is hydroxymethylene [--CH(OH)-]. In this instance, unless thehydroxyl group is protected, as by formation of a lower acyl ester, itis oxidized to form a carbonyl group. Similar oxidation is effected whencompound (Ic) contains as Y a 3-hydroxybutyl group. A hydroxylatedproduct is readily obtained, however, by hydrolysis of a product ester.The reaction temperature is not narrowly critical, and temperatures inthe range of'from C. to about 75 C. are suitable, although ambienttemperatures are preferred.

In the second step, bicyclic compound (X) is treated with acid or baseto effect cyclization to (XI). In this reaction,--it is preferred thatthe Water of reaction be removed, as by refluxing the reaction mixturewith an azeotroping agent in the presence of a strong acid andseparating the water from the condensate. Suitable strong acids aresulfuric acid, p-toluenesulfonic acid, potassium bisulfate and the like.Alternatively, base catalyzed dehydration can be utilized, for example,by refluxing compound (X) in the presence of methanolic sodiumhydroxide.

The hydrogenation of cyclo-olefin XI to tricyclic compounds XV or XII ispreferably effected with a noble metal 22 catalyst, e.g., apalladium-charcoal catalyst or a rhodium catalyst. In formula XV Rrepresents hydrogen or alkyl. Thus, when compounds of formula XI whereinY represents hydrogen or alkyl are hydrogenated, compounds of formula XVare obtained, whereas when compounds of formula XI wherein Y representshydrogenation yields compounds of formula XII. Hydrogenation products offormula XI are converted to retrosteroids by base catalyzed reactionwith methylvinyl ketone to yield a 95,10u-androst-4-ene-3-one of formulaXVIII. The conversion of compounds of formula XI to compounds of formulaXV and of the latter to compounds of formula XVIII are described ingreater detail in Belgian Pat. No. 663,197.

Compounds of formula XI wherein Y is R can also be directly reacted withmethyl vinyl ketone yielding a 5- hydroxy-tetracyclic compound offormula XVI. These latter compounds can then be subjected to dehydrationfollowed by hydrogenation or to hydrogenation followed by dehydration toyield 9-,10aor l0a-steroids of formulas XVII and XVIII. These proceduresare described in greater detail in Netherlands Octrooiaanvrage No.6412939. Still other methods of utilizing compounds of formula XI aredescribed in the literature and other patents.

In those compounds of formula XI wherein Y is a 3- substituted butylradical, catalytic hydrogenation over a noble metal catalyst such aspalladium gives a 19-nor-4,5- seco compound of formula XII. The3-su=bstituted butyl radical is then converted to a 3-oxobutyl radical,thus giving a compound of formula XIII.

The conversion of the 3-substituted butyl radical of the compound offormula X II to the 3-oxobutyl radical of the compound of formula XIIIcan be effected for each particular meaning of R and R in a manner knownper se as described hereinabove for generation of a 3-oxobutyl moiety incompounds of formula I. When R and R taken together are alkylenedioxy,the conversion of compounds of the formula XII to compounds of theformula XIII proceeds directly in the presence of acid, e.g.hydrochloric acid or sulfuric acid and acetone at room temperature.

However, the conversion of the 3-substituted butyl radical of thecompounds of formula XII to the 3-oxobutyl radical of the compounds offormula XIII for other specified values of R and R defined hereinafter,proceeds through a reaction sequence which yields novel intermediates.When R taken alone is etherified hydroxy e.g. lower alkoxy and R takenalone is hydrogen; compounds of formula XII, for example,10[3-tertiary-butoxybutyl]-18-methyl 19 nor-desA-androstan 5,17 dione,can be converted by cyclization to a novel class of enol ethers of theformula:

5 E a); r t l MVRn 12 XIX wherein R R 11, R R R Z and m are as above.

wherein R R R11, R12, R R R Z and m are as above.

Exemplary of compounds of this formula is 6a,9a-trans-2- methyl Gaflethyl 7 oxo-perhydrocyclopenta[5,6]- naphtho[2,1-b]pyran-1 la-ol.

The compounds of formula XX can be further reacted by an oxidationprocess to produce the diketone compounds of structure XIII. Moreover,where R in formula XX is ethyl, i.e., 6a,9a-trans 2methyl-6afi-ethyl-7-oxoperhydrocyclopenta[5,6]naptho [2,1-b1pyran 11aol, the oxidation reaction affords the novel compound [3-ox0-butyl]-18-methyl 19 nor desA androstan 5,17-dione. Exemplary of thesuitable oxidizing agents for the reaction, are chromic acid andpotassium dichromate. Jones Reagent (chromic acid, sulfuric acid andacetone). is an especially preferred reagent for this purpose. Thereaction is carried out in the presence of a mineral acid such ashydrochloric acid or sulfuric acid at room temperature.

Cyclization of the compounds of formula XIII can then be effected toyield l9-nor-androst-4-ene-3-one of the formula X'IV. The cyclizationreaction of compounds of formula XIII to compounds of formula XIV can beeffected by treatment of the compound of formula XIII with acid or base.In this reaction it is preferred that the water of reaction be removed,as by refluxing the reaction mixture with an azeot-roping agent in thepresence of a strong acid and separating acid, p-toluenesulfonic acid,potassium bisulfate and the like. Alternatively, base-catalyzeddehydration can be utilized, for example, by heating compound XII'I inthe presence of methanolic sodium hydroxide or potassium t-butylate int-butanol to about 50 C. Moreover, where R in formula XIH is ethyl, forexample, 10-[3-oxo-butyl]-1S-methyl-l9-nor-desA-androstan-5,17-dione,the cyclization process yields the novel 18-homo di keto compound13fl-ethyl-gon 4 cue-3,17- dione.

Compounds of formula XIV can be selectively alkynylated 'by a suitableorgano metalic acetylide affording norgestrel (13/3-ethyl-17u-ethynyl l7hydroxy-gon-4-ene-3- one). Exemplary of the suitable al'kynylatingagents to effect the conversion to norgestrel are the alkali acetylidessuch aslithium acetylide, potassium acetylide, sodium acetylide, etc.The reaction is carried out in the presence of' liquid ammonia in asuitable solvent system such as for example, benzene or toluene. Thealkynylation is effected preferably at the reflux temperature of thereaction medium although temperatures from between 60 to -30 aresuitable. Exemplary of other suitable reagents to effect the acetylenicaddition are lithium acetylide ethyl magnesium halides. The acetyleneaddition, known with 13-methy1-substituted steroids, is similarlyeffected with the more bulky 13-ethyl-substituted steroidnotwithstanding the increased steric hindrance in the latterconfiguration.

The above and other methods for utilizing compounds of formulas XII andXIII as intermediates in syntheses of steroidal materials are describedin publisched patents and in the literature, such as French Pat. Nos.1,364,556; 1,452,898; 1,432,569 and 1,465,400,

In an alternate procedure not depicted in the subject reaction schemecertain compounds ;,of, formula XI wherein Y is S-hydroxybutyl oranether or-ester protected derivative thereof can be converted to eholethers of formula XIX via novel dienol ethers of formula XXV accordingto the following scheme? i Rn RBO XI-a wherein Z, R R R R R and R are asabove and R' is hydrogen, lower alkyl, acryl, monocyclic carbocyclicaryl-lower alkyl or a radical of the formula wherein each of R R and Rindependently is lower alkyl.

It is to be understood, that compounds of formula XI-a wherein R' isother than hydrogen, lower alkyl or ac'yl can be readily prepared fromcompoundsi of formula XI wherein R is hydroxy by reacting the lattercompound with a halo derivative of the radical to be introduced such asa monocyclic carbocyclic aryl lower alkyl halide or where X is halousing conditions otherwise well known in the art for such reaction.

As used above the term monocyclic carbocyclic aryl denotes a phenyl orsubstituted phenyl radical. Substi-- tuted phenyl radicals have one ormore of the same or different substituents attached to any positionavailable. for substitution. Substituents on the aryl groupmay include,for example, lower alkyl, e.g. methyl,ethyl. and

the like; etherified hydroxyhsuch as, lower alkoxy, e.g.,

methoxy, ethoxy, and the like. The termmonocyclic carbocyclic aryl-loweralkyl comprehends, for, example,

phenyl-lower alkyl, e.g., benzyl, l-phenylethyl, 2-phenyl-' ethyl, andthe like included aryl substituted derivatives thereof.

In step (a) of the subject reaction scheme the -[3- substituted-alkyl]-A-desA-steroids of Formula XI-a are-cyclized to yield the novel dienolether compound of formula XXV. The cyclization is, suitably effected bythe application of heat in the presence of a mineral acid, such assulfuric acid or hydrogen halides, e.g., hydrochloric acid; or,anorganic acid, preferably an aryl sulfonic acid such as benzenesulfonic acid or p-toluene sulfonic acid. The cyclization reaction canbe conducted in any suitable inert organic solvent, preferably however,a hydrocarbon such as benzene'or toluene is employed. The reactionisconveniently carried out at the reflux temperature ofth'e'solventalthough lower reaction tempratures" can also be employedconsistent with carrying out the reaction in a-rninim'um of time withoutundue ditficulty.When R in the compounds of formula XI-a is hydrogen theaforesaid cyclization can be effected by the application of heat alone,acid treatment alone or a combination of both.

In step (b) of the subject scheme dienol ether compounds of formula XXVare converted into enol ether compounds of formula XIX by a novelselective hydrogenation procedure. The hydrogenation can be suitablyeffected by employing a noble metal catalyst such as, palladium,platinum and rhodium with the preferred catalyst being palladium. It'ispreferred to deposit the catalyst on a suitable support material, carbonbeing found torbe most convenient for the purpose. The hydrogenation issuitably conducted in the presence of an inert organic solvent,preferably a hydrocarbon such as benzone or toluene. Ambient conditionsof room temperature and atmospheric pressure are generally preferred toavoid significantjhydrogenation of the A bond. The hydrogenation must-beeffected under basic conditions. A most suitable base has been found tobe a tri-lower alkylamine. such as triethylamine.

Compounds of formulae XI, XIV, XV-II, XVIII, XIX XX wherein Z iscarbonyl can be converted into corresponding pregnane compounds, i.e.,compounds in which Z is of the formula by known procedures. Thus, forexample, 19-nor-14B- androst-4-ene-3,l7-dione can be converted intol9-nor- 14,3,17q-progesteibne and desA-androst-9-ene-5,17-dione can beconverted into desA-pregn-9-en-5-one. These procedures for convertingandrost-l'l -ones into pregnanes arebest effected if all carbonyl groupsother than that in the :17-POSIIIOI1 are initially protected.

As has been pointed out above, the products of this invention areproduced in the form of various optically active antipodes, which can becarried through the entire reaction sequence, 'or which can be resolvedat suitable places during the reaction sequence. For example, at anystage wherein a compound havinga secondary hydroxyl group is present,such as hydroxytetrahydropyran (IV), or any of the hydroxy compounds offormula I, one can reactthe secondary alcohol with a dicarboxylic acidto form a half-ester. Suitable dicarboxylic acids include lower allryldicarboxylic acids such as oxalic acid, malonic acid, succinic acid,glutamic acid, adipic acid, or aromatic carboxylic acids such asphthalic acid. The resulting halfaester is then reacted with anoptically active base, such as brucine, ephedrine, or quinine, toproduce a diastereomeric salt. The salts, after separation, are thenreadily reconverted to optically active alcohols. As an alternative, thesecondary alcohol can be reacted with an opticallyactive acid, forexample, camphorsulfonic acid. The resulting,diastereomeric, esters arethen separated and reconverted to the alcohols.

It isf'preferred that the resolution be effected at some stage in thesynthesis of alken-3-one, as by the abovementioned resolution ofhydroxytetrahydropyran (IV). In a more preferred technique opticallyactive 5-alkyl-5- valerolactone is obtained from 5-alkyl-5-oxopentanoicacid via known microbiological processes. The S-form of this lactone isthe preferred form for use in accordance with this invention. In a thirdmethod, the racemic lactone can be hydrolyzed to the correspondinghydroxy acid, which is then resolved by treatment with an opticallyactive base in the manner described above. Still other methods will beapparent to those skilled in the art. Resolution at such early stages inthe overall process described herein is highly preferred because of theimproved efficiency in the production of steroids having a desiredstereo-configuration. Because the stereo-configuration is retainedthroughout the synthesis of alken-3-one (II), and further because thecondensation of alken-3-one or variant (II, IIa or IIb) withcycloalkanedione (III) is stereospecific, one, by proper selection ofstereo-isomers at these early stages, can ensure that substantially allof the tricyclic compounds of this invention and the steroids derivedtherefrom have a selected stereo-configuration. Thus, by this technique,the production of compounds of the undesired configuration is minimizedor prevented entirely, with an attendant increase in the efiiciency ofthe production of compounds of the desired configuration.

In the claims, all compounds shall be construed to in clude,independently, the racemic form of the compound and independently, eachenantiomeric form, i.e., the d and l configurations unless specificallyindicated otherwise.

The following examples are illustrative. All temperatures are in degreecentigrade and all products having centers of asymmetry are racemicunless specifically indicated otherwise.

EXAMPLE 1 (a) A mixture of 38 grams of 2-methylcyclohexane- 1,3-dione,51 grams of sodium hydroxide, and 450 milliliters of water washydrogenated over Raney nickel catalyst at a maximum temperature of C.and a maximum pressure of 750 p.s.i. The reaction mixture was filteredand the filtrate, containing sodium S-hydroxyheptanoate, was acidifiedwith concentrated hydrochloric acid (to a pH of 1), and then refluxedfor 30 minutes. The resulting solution was cooled and filtered. Thefiltrate was extracted with three l-liter portions of benzene and thecombined benzene extracts, after washing with water, drying over sodiumsulfate, and evaporation, yielded 26 grams of S-ethyl-S-hydroxyvalericacid lactone.

(b) A suspension of 5.2 grams of lithium aluminum hydride in 250milliliters of anhydrous ether was added with stirring over one hour toa solution of 64 grams of S-ethyl-S-hydroxyvaleric acid lactone in 500milliliters of anhydrous ether maintained at 0-5 C. and under a nitrogenatmosphere. After the addition of 250 milliliters of 3 N sulfuric acid,the reaction mixture was extracted with three lOO-milliliter portions ofether. The combined ether extracts were then washed with twoIOU-milliliter portions of sodium bicarbonate solution, then with twoISO-milliliter portions of water. After drying over sodium sulfate, theetheric solution was evaporated at 45 C. under vacuum to yield 57.1grams of 6-ethyl-2-hydroxytetrahydropyran.

(c) To 7.6 grams of magnesium in 7 milliliters an hydroustetrahydrofuran containing a few drops of ethylbromide and a few.milligrams of iodine maintained at 45-48 C. was added, over a four-hourperiod, 120. milliliters of a 20.8 weight percent solution of vinylchloride-in tetrahydrofuran. The resulting reaction mixture was cooledto 30 C. and a solution of 13 gramsof 6-ethyl-2 washing with threeIOO-milliliter portions of sodium chlo+ 27 ride, drying over sodiumsulfate, and evaporation gave 16 grams of 3,7-dihydroxy-1-nonene.

(d) To a solution of 25 grams of 1-nonene-3,7-diol in 1250 millilitersof 1,2-dichloroethane was added 0.25 gram of hydroquinone and 300 gramsof manganese dioxide. The resulting slurry was stirred vigorously forone hour without heating, during which time the reaction temperaturerose to about 30 C. The resulting reaction mixture was filtered and themanganese dioxide filter cake was washed thoroughly with 500 millilitersof 1,2-dichloroethane. The combined filtrates were evaporated in vacuoat 40 C. to yield 17.3 grams of 7-hydroxy-1-nonen-3-one. This compoundis reacted with hydrogen chloride to produce1-chloro-7hydroxynonan-3-one, with dimethylamine to produce 1(N,N-dimethylamino)-7-hydroxy-nonan-3- one, with water to produce1,7-dihydroxynonan-3-one, or with ethanol to produce1-ethoxy-7-hydroxynonan-3-one.

EXAMPLE 2 Employing procedures similar to those described in Example 1,except that cyclohexane-1,3-dione is substituted forZ-methylcyclohexane-1,3-dione, 7-hydroxyoct-1-en-3- one is produced.

- EXAMPLE 3 Employing procedures similar to those described in Examplel, except that Z-ethylcyclohexane-1,3-dione is substituted forZ-methylcyclohexane-1,3-dione, 7-hydroxydec- 1-en-3-one is produced.

EXAMPLE 4 A 20 percent solution of diisobutyl aluminum hydride in 31.4milliliters of toluene was added over a 30-minute period to a solutionof 5 grams of L-( )-5-pentyl-5-hydroxy-valeric acid lactone in 50milliliters of toluene at -70 C. After workup of the resulting reactionmixture as described in Example 1(b), there was obtained 5 grams ofpractically pure optically active 6-pentyl-2-hydroxytetrahydropyran.

To a solution of this product in 20 milliliters of tetrahydrofuran wasadded at 30 C. a solution of vinyl magnesium chloride in tetrahydrofuranprepared from 3.5 grams of magnesium and excess vinyl chloride in themanner described in Example 1(c). After hydrolysis of the reactionproduct with an ammonium chloride-ice mixture, followed by extractionwith ether, there was obtained 5.72 grams of3(R,S),7(S)-dihydroxy-1-dodecene as an oil. After crystallization fromisopropyl ether-pentane at C., the diol melted at 65.5-67.5 C. and hadan optical rotation [a] =f+5.9 as determined from a 1 percent solutionin chloroform.

A solution of 5.22 grams of the diol in 1,2-dichloroethane was stirredwith 63 grams of manganese dioxide in the presence of 50 milligrams ofhydroquinone for one hour. After filtration to remove the manganesedioxide, washing with additional dichloroethane and ether, andevaporation of the filtrate at 30 C., there was obtained 3.98 grams ofoptically active 7(S)-hydroxy-1-dodecen-3- one.

EXAMPLE A solution of racemic 7-hydroxy-1-nonen-3-one [21.3 g.; crudeobtained as in Example 1(d)] in hexane (200 gave unpolar by-products.Hexane-ethe'r(4:1)-, (1:1), and straight ether then eluted2-[2-(1-phenylethy1amino) ethyl] 6 ethyl 2 tetrahydropyranol obtained insolid form after evaporation of the solvents.

EXAMPLE 6 To a solution of the 2-[2-(l-phenylethylamino)ethyl]-6-ethyl-2-tetrahydropyranol (prepared and purified as de-- scribed inExample 5; 13.87 g., purified by chromatography) in dioxane (200 ml.) asolution of oxalic-acid (4.55 g.; 99.0% anhydrous powder) in dioxane(215 ml.) was added. After standing at 25 C. (65 hours) the precipitatedwhite crystals were filtered off and washed with cold dioxane (20 ml.).Thus, the oxalate of 2-[2-(1-phenylethylamino)ethyl]-6(S)-ethyl-2-tetrahydropyranol was obtained, M.P.123-128, [a] =-28.2 (c.=1.0; methanol).

EXAMPLE 7 To 20 g. of magnesium turnings in a 500 ml. flask equippedwith Dry-Ice condenser, thermometer, and dropping funnel, 30 ml. oftetrahydrofuran was added followed by dropwise addition of vinylchloride solution (200 ml.; 26% solution in tetrahydrofuran) while theoil bath in which the flask was immersed was maintainedat 70. The vinylchloride was added at such a rate so that the reaction temperatureremained at 46-52". Iodine vapor and methyl iodide were used to initiatethe reac:

drous sodium sulfate. Removal of the solvent invacuo aiforded crude11,11 ethylenedioxy 3,7 dihydroxy-ldodecene as pale yellow liquid whichsolidified upon refrigeration.

A sample of the crude product was recrystallized once from isopropylether-hexane to give clusters of colorless needles which upon threeadditional recrystallizations from the same solvent provided11,l1-ethylenedioxy-3,7- dihydroxy-l-dodecene which melted at 52-54. I

A solution of 22.0 g. of 11,11-ethylenedioxy-1- dodecene-3,7-diol inbenzene (600 ml.) and diethylamine (40 ml.) was treated under vigorousstirring with manganese dioxide (108 g.) at 25 C. After stirringfor 18hours at room temperature, the manganese dioxide was filtered off andWashed with benzene. After evaporation of the filtrate crude2-(2-diethylaminoethyl)-6-(4,4-ethylenedioxypentyl)-2-tetrahydropyranolwas obtained.

A sample of the crude 11,1l-ethylenedioxy-3,7-dihydroxy-l-dodecene (10g.; prepared as described above) was dissolved in dichloroethane (250ml.), and to this solution activated manganese dioxide (60 g.) wasadded.

The mixture was stirred for 1 hour at room temperature, filtered, andthe filter cake washed three times, each time with 250 ml. ofdichloroethane. Concentration of g the combined filtrate aiforded crude11,11-ethylenedioxy 7- hydroxy-1-dodecen-3-one.

EXAMPLE 8 A mixture of 8.3 grams of 7-hydroxy-1-nonen-3-one, 7 grams ofZ-methylcyclopentane-1,3-dione, 0.1 gram of hy-' droquinone, 4.2milliliters of pyridine, and 42 milliliters of toluene was refluxedunder a nitrogen atmosphere for two hours'employing a Dean-Starkwater-collection apparatus. The reaction solution, after cooling, wasfiltered to recover unreacted Z-methylcyclopentane-1,3-dione. The

filtrate was evaporated to dryness, yielding 9.78 grams of' crude3-ethyl-6aB-methyl-1,2,3,5,6,6a-hexahydrocyclopensolution wasconcentrated and 20 milliliters of hexanewas added to causecrystallization. A first cropof 3.88 grams was obtained which meltedat96-99 C. After con centration of the mother liquor and crystallizationfrom" a cold'diisopropyl ether/hexane mixture, a second crop ofcrystalsmelti'rlg'at 100 103 C. was obtained.

Eiri'ploying' similar procedures S-ethyl-6afi-methyl-1,2,3,'5,6,6a-hexahydroeyelopenta [f] [-1 benzopyran-7 8H)-one is repared; bysubstituting -1=tzhl0ro-7-hydroxynonan-3- one for the7-hydroxy-'l-nonen-3-one.

. Q EXAMPLE'9 I A'mixture of--.l6.2 grams of 7-hydroxy-1-nonen-3-one,11.5 grams of 2-methylcyclopentane-1,3-dione, 210 milliliters ofxylene,'and 105.1nilliliters of acetic acid was re fluxed for l /zhours.Aftersevaporation, the crude reaction product, weighing 27.9..grams, wasextracted with two 135-milliliter portions of benzene. The remainingresidue, which weighed 1.7 grams, was unreacted2-methylcyclopentane-l,3-dione. The benzene extracts were combinedand'evaporated to yield 25 grams of crude productsA'solution of this.product in hexane was filtered through alumina and; after evaporation ofthe hexane and crystallization of theproduct from a hexane-pentanemixture, there wasobtained 16.6 grams of3-ethyl-6a}3-methyl-1,2,3,5,6,6a .hexahydrocyclopenta[f] [1]benzopyran-7(8H)-one, melting'point 104-106 C.

Employing similar procedures-3-ethyl-6afl-methyl-1,2,3, 5,6,6ahexahydrocyclopenta[f] [1]benzopyran 7(8H)- one is prepared bysubstituting 1-(N,N-dimethylamino)- 7-hydroxynonan-3-one for the7-hydroxy-1-nonen-3-one.

V ,7 EXAMPLE'IO A mixture of 1.56 grams of 7-hydroxy-1-nonen-3-one, 1.12grams of ;2-methylcyclopentane-1,3-dione, and 50 milliliters of toluenewas refluxed .for 6 hours. Workup of the reaction mixture in the mannerdescribed in Example 9 yielded3-ethyl-6aB-methyl-1,2,3,5,6,6a-hexahydrocyclo penta [f] [1]benzopyran-78H) -one.

EXAMPLE 11 A mixture .of 1.56 grams of 7-hydroxy-1n0nen-3-one, .l.12.grams of 2-methylcyclopentane-l,3-di0ne, 16 milliliters of p-dioxane,and 80 milligrams of p-toluenesulfonic acid was reacted at 25 C. .for 22hours. Employing the work-up procedures of Example 9, there was obtained3- ethyl-6'a;3-methyll,2,3,5,6,6a-hexahydrocyclopenta [f] l] benzopyran-7(8H)-one. I

. I EXAMPLE 12 A mixture of" 1.56 grams of 7-hydroxy-1-nonen-3-one, 1.12grams or 2-methylcyclopentane-1,3-dione, 0.16 gram of p-toluenesulfonicacid, and 16 milliliters of benzene was refluxed for 30 minutes andworked up as described in Example 9 to yield 3-ethyl-6a/i-methyl-1,2,3,5,6,6ahexahydrocyclopenta[f]'[1]benzopyran-7(8H)-0ne.

EXAMPLE 13.

" A mixture of 1,56 grams of 7-hydroxy-1-nonen-3-one, 1.12 grams of2-methylcyclopen'tane-1,3-dione, 16 milliliters of toluene, 0.8milliliter of'pyridine, and 0.16 grams of p-toluen'esulf'onie' acid wasrefluxed for 30 minutes.

After treatment of the reactionmixture as described in Example :9, there.was obtained 3-ethyl-6afi-methyl-l,2,3,

.5 ,6 ,6a hexahydrocyclopenta [f [1]benzopyran 7 (8H) one. *1

EXAMPLE 14.

zopyran-7(8H)-one, melting point 100-102 C.

. MP E ,.A mixture eonsisting1581.56 grams of 7-hydroxy-I- nonen-3-one,1.12 grams of'2 methylcyclopentane-1,3- dione, and 0.16 gram ofpotassium acetate in tert.-butanol,

was held at 25 C. for 20 hours. The resulting reaction mixture wasextracted with three ZOO-milliliter portions of ether. After washingeach ether extract with three 100- milliliter portions of water, theether extracts were combined, dried over sodium sulfate, filtered, andevaporated to dryness. The residue which weighed 2.16 grams wasdissolved in 22 milliliters of hexane and chromatographed on alumina.After elution with hexane and evaporation of the hexane, there wasobtained spiro[4a-methyl-7a-hydroxy2,3,4,4a,5,6,7,7a-octahydrocyclopenta[b]pyran-5 one2,2'-(6'-ethyltetrahydropyran)l, melting point 88- 95 C. The meltingpoint was 93-97 C. after sublimation at 65 C. and 0.01 mm.

EXAMPLE 16 A mixture of 0.3 gram of 7-hydroxy-l-nonen-3-one, 0.3 gram of2-methylcyclopentane-1,3-dione, 6 milliliters of tert.-butanol, and 15milligrams of sodium hydroxide was held at 25 C. for 2 /2 days yieldingspiro[4a-methyl-7ahydroxy 2,3,4,4a,5,6,7,7a-octahydrocyclopenta[b]pyran-5-one-2,2'-(6-ethyltetrahydropyran)]. The same product was obtained whenpotassium hydroxide was substituted for sodium hydroxide.

EXAMPLE 17 A mixture of 0.3 gram of 7-hydroxy-1-nonen-3-one, 0.3 gram of2-methylcyclopentane-1,3-di0ne, 6 milliliters of toluene, and 0.1milliliter of a 30 percent solution of benzyl trimethyl ammoniumhydroxide in methanol was held at 25 C. for 5 /2 days and then heated at50 C. for 15 hours yielding spiro[4a-methyl-7a-hydroxy-2,3,4,4a,5,6,7,7a octahydrocyclopenta [b]pyran-5-0ne-2,2-(6'-ethyltetrahydropyran) EXAMPLE 18 A mixture of milligrams ofspiro[4a-methyl-7-hydroxy 2,3,4,4a,5,6,7,7aoctahydrocylopenta[b]pyran-5- one-2,2'-(6-ethyltetrahydropyran)], 5milliliters of benzene, and 10 milligrams of p-toluenesulfonic acid washeld at 25 C. for 20 hours. After workup in the manner described inExample 15 and crystallization from hexane, there was obtained pure3-ethyl-6aB-methyl-1,2,3,5,6,6ahexahydrocyclopenta [f l benzopyran-7 8H)-one.

EXAMPLE l9 Employing apparatus and procedures similar to those describedin Example 8, except that 2-ethylcyclopentane- 1,3-dione is substitutedfor 2 methylcyclopentane-1,3- dione, there is produced3,6aB-diethyl-1,2,3,5,6,6a-hexahydrocyclopenta [f]1]benzopyran-7(8H)-one melting at 5759 C.

EXAMPLE 20 Employing apparatus and procedures similiar to thosedescribed in Example 8, but substituting 2-methylcyclohexane 1,3 dionefor 2-methylcyclopentane-1,3-dione, there is producedS-ethyI-GaB-methyl-1,2,3,5,6,6a,8,9-octahydro7H-naphtho[2,1-b]pyran-7-0ne melting at 91 EXAMPLE 21 Employingapparatus and procedures similar to those described in Example 8, butsubstituting 2-ethylcycl0hexane-l,3-dione forZ-methylcyclopentane-1,3-dione, there is produced 3,6at3 diethyl1,2,3,5,6,6a,8,9-octahydro-7H- naphtho[2,1-blPYran-7-one.

EXAMPLE 22 Employing apparatus and procedures similar to those describedin Example 8, but substituting 7 hydroxy-locten-3-one for7-hydr0xy-1-nonen-3-one, there is produced 3,6aBdimethyl-l,2,3,5,6,Gel-hexahydrocyclopenta [f] 1]benzopyran-7(8H)-one.EXAMPLE 23 Employing apparatus and procedures similar to those describedin Example 19, but substituting 7-hydroxy-l- 3-1 octen-S-one for 7hydroxy 1-nonen-3-one and 2-ethylcyclopentane 1,3 dione for2-methylcyclopentane-l,3- dione,,tl1ere is produced6afl-ethyl-3-methyl-1,2,3,5,6,6ahexahydrocyclopenta [f] 1 benzopyran-7(8H) -one.

EXAMPLE 24 Employing apparatus and procedures similar to those describedin Example 8, but substituting 7 hydroxy-1- decen 3-one for7-hydroxy-1-nonen-3-one, there is produced Gapmethyl-3-propyl-1,2,3,5,6,6a-hexahydrocyclopenta[f] [1]benzopyran-7(8H)-one.

EXAMPLE 25 A mixture of the optically active 7-hydroxy-l-dodecen- 3-one,obtained as described in Example 4, 2.25 grams of2-methylcyclopentane-1,3-dione, 50 milliliters of xylene, and 25milliliters of acetic acid was refluxed for 1 /2 hours under a nitrogenatmosphere. After evaporation under vacuum, the residue was extractedwith cold benzene leaving 400 milliliters of unreactedmethylcyclopentanedione as an insoluble residue. The benzene solutionwas then evaporated to yield 5.56 grams of optically active 3-pentyl-6aB-methyl- 1,2,3,5,6,6a-hexahydrocyclopenta [f] 1]benzopyran-7(8H) one. After chromatographing the crude product onalumina, followed by crystallization from methanol-water, the productmelted at 60-61 C., [@15 166.

EXAMPLE 26 A mixture of 2-methyl-cyclopentane-1,3-dione (2.24 g.),xylene (100 ml.) and glacial acetic acid (25 ml.) was refluxed under anitrogen atmosphere for 2 minutes. Then optically active2-[2-(l-phenylethylamino)ethyl]-6-ethyl- Z-tetrahydropyranol oxalate(6.4 g., prepared as described in Example 6) was added and the mixturerefluxed for 1 hour. The resultant solution was then Washed with H O (8X50 ml.), saturated NaHCO solution (2x 50 ml.) and H (1x 50 ml.). Theaqueous phases were extracted with benzene (2x 150 ml.). The combinedbenzene and xylene fractions were evaporated and the residue (2.4 g.)was chromatographed on alumina (160 g.). With hexane andhexan-ether-(19z1) (total 13 fractions, 160 ml. each) pure3-ethyl-6ap-methyl1,2,3,5,6,6a-hexahydro-cyclopenta [f][1]benzopyran-7(8H)-one was eluted. After evaporation of fractions 13-11(pure by thin layer chromatography analysis) yellow crystals resulted.This product had a rotation of [M 145.3 (c.=1.0; CHClg).Recrystallization from pentane afforded 3-ethyl-6afi-methyl-1,2,3,5,6,6a hexahydro-cyclopenta[f] [1]benzopyran 7(8H)-one as beige crystalsM.P. 97100, 145.7 (c.=1.0; CHCl EXAMPLE 27 A mixture of Z-methylcyclopentane-1,3-dione (8.6 g.), xylene ('157 ml.) and glacial aceticacid (78.5 ml.) was refluxed under a nitrogen atmosphere for 2 minutes.Then a solution of crude 2-(2-diethylaminoethyl) -6-(4,4-ethylenedioxypentyl)-2-tetrahydropyranol (23 g., as prepared in Example 7)in xylene (78.5 ml.) was added to the reaction mixture during minutes.The mixture was then refluxed for another 15 minutes and then worked upby extraction with ether (3 times), washing of the combined extractswith sodium bicarbonate solution and water, drying over sodium sulfate,filtration, and evaporation of the filtrate at 50 C. in' vacuo to give acrude mixture of 3- (4,4 ethylenedioxypentyl)-6a,B-methy1-1,2,3,5,6,6a-hexahydrocyclopenta[f][l]benzopyran 7(8H) one,4-(3- hydroxy 7 oxooctyl) 7ap methyl-2,3,5,6,7,7a-hexahydroinden- 1,5(1H) dione and 3 (4 oxopentyl)-6aflmethyl 1,2,3,5,6,6ahexahydrocyclopenta[f] [l]benzopyran-7(8H)-one. This mixture wasseparated by chromatography on alumina. Elution with hexane aiforded 3-(4,4 ethylenedioxypentyl) 6a;8 methyl 1,2,3,5,6,6ahexahydrocyclopenta[f][1]benzopyran 7(8H) one, elution with hexane-ether (9:1) afforded 3-(4oxopentyl)- 6a methyl 1,2,3,5,6,6a hexahydrocyclopentafi] [1]- 32benzopyran 7(8H) one and elution with chloroform aflorded 4(3-hydroxy-7-oxooctyl)-7a;8-methyl-2,3,5,6,7,7a-hexahydroinden-1,5(1H)-dione, an oil. f

A mixture of pure 3-(4,4-ethylenedioxypentyl)6a methyl 1,2,3,5,6,-6ahexahydrocyclopenta[f] [1]benzopyran-7(8H)-one (2.86 g.), acetone(56'ml.) and 1 N sulfuric acid (5.6 ml.) was allowed to stand at roomtemperature for 18 hours. The workup by extraction with ether (3 times),washing of the combined extracts with sodium bicarbonate solution andwater, drying over sodium sulfate, filtration, and evaporation of thefiltrate at 50 C. in vacuo gave a crude mixture of 4-(3-hydroxy-7-oxooctyl) 7a}? methyl 2,3,5,6,7,7a hexahydroinden 1,5 (1H)-dione and3-(4-oxopentyl)-6aflmethyl-1,2,3,5,6, 6a-hexahydrocyclopenta[f][1]benzopyran 7(8H) one. This mixture was separated by chromatography onsilica gel (52 g.). Elution with hexane-ether (1:1) and ether aloneafforded pure 3-(4'oxopentyl)-6aB-methyl-1,2,3,5,6,6a-hexahydrocyclopenta[f] [1]benzopyran 7(8H) one (M.P. 74-85 C., thinlayer chromatography, one spot). Elution with methanol afforded4-(3-hydroxy-7-oxooctyl)- 7a[3-methyl-2,3,5,6,7,7a-hexahydroinden 1,5(lH)-dione as an oil (thin layer chromatography, one spot).

A mixture of 4-(3-hydroxy 7 oxooctyl)-7a5-methyl-2,3,5,6,7,7a-hexahydroinden-1,5 1H)-dione (1.7 g.), benzene (50 ml.) andp-toluenesulfonic acid (170 mg.) was refluxed for 2 hours. The workup byextraction with ether (3 times), washing of the combined extracts withsodium bicarbonate solution and water, drying over sodium sulfate,filtration, and evaporation of the filtrate at 50 C. in vacuo gave crude3-(4-oxopentyl)-6afi-methyl-l,2,3,5,6,6a-hexahydrocyclopenta[f][1]benzopyran 7(8H) one which waschromatographed on alumina (46.5 g.). Elution with hexane-benzene (9:1),(4:1), (1:1) and (1:2) afforded pure 3-(4-oxopentyl) Gapmethyl-1,2,3,5,6, 6ahexahydrocyclopenta[f] [1]benzopyran 7(8H)-one (thinlayer chromatography, one spot).

EXAMPLE 28 A solution of3-(4-oxopentyl)-6a,8-methyl-1,2,3,5,6,6ahexahydrocyclopenta[f][l]benzopyran-7(8H) one (1.36 g. in tetrahydrofuran (60 ml.) was addedat 0 C. within 15 minutes to a mixture of lithium aluminum hydride (262mg.) in tetrahydrofuran (40 ml.), with stirring and under a nitrogenatmosphere. The reaction mixture was stirred for an additional 30minutes at 0 C. and then worked up by careful addition of water,filtration and evaporation of the filtrate in vacuo at 38 C. yieldingcrude 3-(4-hydroxypentyl) 621B methyl-1,2,3,5-,6,6a,7,8=-octahydrocyclopenta[f] [1]benzoypyran-7-ol (thin layer chromatography,one spot) was obtained.

EXAMPLE 29' A solution of 1 gram of3-ethyl-6a;8-methyl-1,2,3,5,6,6ahexahydrocyclopenta[f][1]benzopyran-7(8H)-one in 20 milliliters of tetrahydrofuran was addedover a 15-minute period to a stirred mixture of milligrams of lithiumaluminum hydride in 25 milliliters of tetrahydrofuran maintained at 0 C.and under a nitrogen atmosphere; After stirring at 0 C. for anadditional hour, a few drops of concentrated sodium hydroxide solutionwas added. The resulting solution was filtered and evaporated to give0.982 gram of 3-ethyl-6aB-methyl-1,2,3,5,6,6a,7,8-octahydrocyclopenta[f][1]benzopyran 7 ol'melting at 107-' 109 C. p

Treatment of 235 milligrams of the product for 20 hours at roomtemperature with 0.28 gram of benzoyl chloride in 2 milliliters ofpyridine as a solvent yielded the 7-benzoate ester.

Treatment of 200 milligrams of the product alcohol for 20 hours at 25 C.with 0.5 milliliter of acetic anhydride' in 1 milliliter of pyridineyielded the 7-acetate.

33 EXAMPLE so Employing procedures similar to those described in Example29 but substituting 3,6afl-diethyl-1,2,3,5,6,6a-hexahydrocyclopentaIf][1, benzopyran -7(8H)-one for the 3- ethyl 6aB methyl 1,2,3,5,6,6ahexahydrocyclopenta- [f] [1]benzo.pyr an-7 (8H)-one, 3,6afl-diethyl1,2,3,5,6,6a, 7,8 octahydrocyclopenta[f] [llbenzopyran 7 01 is produced.

1 EXAMPLE 31 In a manner similar to that described in Example 29,3,6afi-dimethyl 1,2,3,5,6,6a hexahydrocyclopenta [f] [1]benzopyran-7(8H)-one is reduced to its corresponding alcohol. 1

EXAMPLE 32 Employing procedures similar to those described in Example29,6aB-methyl-3-propyl-1,2,3,5,6,6a-hexahydrocyclopenta[f][1]benzopyran-7(8H)-oneis reduced to 6a,?!- methyl-3-propyl 1,2,3,5,6,6a,7,8octahydrocyclopenta- [f] [1]benzopyran-7-ol.

EXAMPLE 33 Employing procedures similar to those described in Example29, except that 3-ethyl-6a/3-methyl-1,2,3,5,6,'6a,8,9- octahydronaphtho[2,1-b]pyran-7-one is substituted for the 3-ethyl-6aB-methyl1,2,3,5,6,6a hexahydrocyclopenta- [f][1]benzopyran-7(8H)-one, there isproduced 3-etbyl- 6a 8 methyl 1,2,3,5,6,6a,8,9 octahydro-7H-naphtho-[2,1-b]pyran-7-ol.

EXAMPLE 34 In a manner similar to that described in Example 29, 2,6afldiethyl 1,2,3,5,6,6a,8,9 o ctahydro-naphtho[2,1- b]pyran- 7-one isreduced to its corresponding alcohol.

EXAMPLE 35 A solutionof a 1.37-gram portion of the optically active enolether produced as described in Example 25 in 25 milliliters oftetrahydrofuran was added over a 15-minute period to a stirred solutionof 137 milligrams of lithium aluminum hydride in 30 milliliters oftetrahydrofuran at C. and under a nitrogen atomphere. After stirring foran additional 30 minutes at 0 C. and the addition of water to thereaction mixture, the mixture was worked upin the'manner described inExample 29 to yield 1.39 grams of optically active3-pentyl-6afl-methyl-1,2,3,4,5, 6,6a,7,-8-octahydrocyclopenta[f][1]benzopyran-7-ol.

EXAMPLE 36 A solution of crude 3-(4-hydroxypentyl)-6aB-methyl-1,2',3,'5,6,6a hexahydrocyclopenta[f][1] benzopyran- 7( 8H)-o1 1.52 g.,obtained by the procedure of Example 28) in pyridine (15 ml.) wastreated with acetic acid anhydride (7.5 ml.) at room temperature. Afterstanding at room temperature for 20 hours the reaction mixture wastreated with methanol (23 ml.) at 0 C. After standing for 30 minutes itwas then extracted with benzene (3 times), the combined benzene extractswere washed with H O, in HCl, saturated NaHCO solution and again with HO. The benzene extract was then evaporated and the residue purified bychromatography on alumina (53.4 g.). Elution with hexane andhexane-ether (9:1) afforded pure 7fi-acetoxy-3-(4-acetoxypentyl)-6a3-methyl-1,2,3,5, 6,6a,7,8 octahydro-cyclopent-a[f][1]benzopyran (thinlayer chromatography, one spot).

EXAMPLE 37 A mixture of 11,1l-ethylenedioxy-1-dodecene-3,7-diol (5.0 g.acetone (100 ml.) and 1 N sulfuric acid (25 ml.) was stirred at roomtemperature for 6 hours. After the workup by extractionv with ether (3times), washing of 34 the combined extracts with sodium bicarbonatesolution and water, drying over sodium sulfate, filtration,-and evaporation of the filtrate at 50 C. in vacuo crude 11-oxo-1-.dodecene-3,7-diol was obtained. This crude productwas used for the nextstep.

A solution of crude 11-oxo-1-dodecene-3,7-diol (3.3 g.) in1,2-dichlorethane ml.) was treated with vigorous stirring with.manganese dioxide (20 g.) at room temperature. After stirring for lhour,the manganese dioxide was filtered off and washed with1,2-dichlorethane. After evaporation of the combined 1,2-dichlorethanefiltrates, crude 7-hydroxy-1-dodecene-3,1l-dione was obtained. Thiscrude product was used for the next step.

A mixture of crude 7-hydroxy-1-dodecene-3,ll-dione (2.6 g.),2-methyl-cyclopentane-1,3-dione (1.6 g.), toluene (35 ml), pyridine (3.5ml.) and hydroquinone (60 mg.) was refluxed with stirring for 2 /2hours. After extraction with ether (3 times), washing of the combinedextracts with sodium bicarbonate solution and water, drying over sodiumsulfate, filtration, and evaporation of the filtrate at 50 C. in vacuocrude 3-(4-oxopentyl)-6a[3- methyl 1,2,3,5,6,6a hexahydrocyclopenta[f][1]benzopyran-7(8H)-one was obtained. This material was chromatographedon alumina (90 g.). Fractions (90 ml. each) were taken as follows.1-4=hexane-benzene (4:1), 5-8 =hexane-benzene (2:1) and 9-12=hexanebenzene (1:1). Fractions 3-12 afforded 3-(4-oxopentyl)-6a 3- methyl1,2,3,5,6,6a hexahydrocyclopenta[f] [1]benzopyran-7 8H) -one.

EXAMPLE 38 10.0 grams of 3,7-dihydroxy-1-nonene was dissolved in 300milliliters of benzene and 20 milliliters of diethylamine (dist). Tothis solution there was added, under vigorous stirring, at 25 C., 60.0grams of activated manganese dioxide. The reaction mixture was thenstirred at 25 C. for 15 hours and then at 45 C. for 5 hours. Themanganese dioxide was then filtered off and the filtrate washed threetimes, each time, with 50 milliliters of henzene. It was then evaporatedto dryness at 45 C. in vacuo yielding a crude product which by thinlayer chromatography (thin layer chromatography system: silica gel Gplates, solvent benzenezdiethylamine 9:1, detection 50 percent aqueouspara-toluenesulfonic acid solution, C. Visibility of desired productl-diethylamino-7-hydroxynonan-3-one can be improved with I vapors) wasshown to contain mainly 1-diethylamino7-hydroxy-nonan-3-one plus tracesof unreacted starting material 3,7-dihydroxyl-nonene. This crude productwas used without purification for the next step.

6.47 grams of Z-methylcyclopentane-1,3-dione, milliliters of xylene and65 milliliters of glacial acetic acid was refluxed for 5 minutes. To theresulting solution there was added under refluxing and a nitrogenatmosphere during 15 minutes a solution of 13.25 grams of theabove-prepared crude product containingl-diethylamino-7-hydroxy-nonan-3-one dissolved in 65 milliliters ofxylene. The reaction mixture was then refluxed for 15 minutes. Theresultant solution was then cooled to 25 C. with an ice bath and thentwice washed, each time with 100 milliliters of H 0, then twice, eachtime with 100 milliliters of saturated NaHCl solution and then againwith 100 milliliters of H 0. The aqueous phases were twice extracted,each time with 200 milliliters of benzene. After evaporation of thecombined xylene and benzene solutions at 55 C. in vacuo, light brownishcrystals were obtained which were diluted with 50 milliliters of hexane,filtered off after 5 minutes, and twice washed, each time with 15milliliters of hexane, yielding dl-3-ethyl 1,2,3,5,6,6a hexahydro6afl-methylcyclopenta[f][1]benzopyran-7(8H)-one (melting point 101-102.5 C., beige crystals were obtained). Further quantities of thisproduct were obtained from the mother liquor by evaporation to drynessand column chromatography using aluminum oxide (40 grams, activity gradeIII) and hexane as a solvent.

35 EXAMPLE 39 .To a freshly prepared solution of methyl lithium (0.2 g.)in tetrahydrofuran (50 ml.), a solution of 3-ethyl- 1,2,3,5,6,6ahexahydro Gap methylcyclopenta[f] [1] benzopyran-7(8H-)-one (1.0 g.) intetrahydrofuran (20 ml.) is added at 20 C. within 20 minutes withstirring and under a nitrogen atmosphere. After stirring for 1 hour at50 C., the'reaction mixture is poured onto ice (50 g.)-ammoniumchloridev g.) Extraction with ether (3 portions, 200 ml. each), washingwith water (3 times, 50 ml. each), drying over sodium sulfate,filtration and evaporation gives 3-ethyl-7a,6aB-dimethyl-l,2,3,5,6,6a,7,8-octahydrocyclopenta[f][1]benzopyran-7-ol which is further purified bypreparative thin layer chromatography on silica gel plates.

EXAMPLE 40 A solution of6a,9a-trans-3-ethyl-1,2,3,5,6,6a,7,8,9,9adecahydro 6aflmethylcyclopenta[f] [11benzopyran-7-ol (1.5 g.) in dimethylformamide (15ml.) is slowly (30 minutes) added at to a stirred mixture of chromicacid (0.3 g.), dimethylformamide m1.) and concentrated sulfuric acid (1drop). Stirring is continued for another 3 hours. After work-up(extraction of the reaction mixture with benzene, washing with water andevaporation of the benzene extracts in vacuo at 40) 6a,9a-trans- 3 ethyl1,2,3,5,6,6a,9,9a octahydro 6afi methylcyclopenta[f][l]benzopyran 7(8H)one is obtained as an oil. After purification by column chromatographyon aluminum oxide, this ketone is dissolved in tetrahydrofuran (25 m1.)and added (within 25 minutes) to a solution of lithium acetylide(prepared from 0.11 g. of lithium wire and acetylene in 50 ml. of liquidammonia) at C. with stirring. Stirring is then continued for 15 hours atthe reflux temperature of the reaction mixture. After adding dryammonium chloride (3 g.) and ether (50 ml.) to the reaction mixture, theammonia was allowed to evaporate. After washing the ether phase withwater (3 times), followed by filtration and evaporation in vacuo at6a,9a trans 7o: ethynyl-3-ethyl- 1,2,3,5,6,6a,7,8,9,9a decahydro Gapmethylcyclopenta- [f] [1]benzopyran-7-ol is obtained as an oil.Purification is achieved by thick layer chromatography on silica gelplates.

EXAMPLE 41 A mixture of 4.9 grams of 3 ethyl 6a 8 methyl-1,2,3,5,6,6a,7,8 octahydrocyclopenta[f] [1]benzopyran- 7-ol produced ina manner similar to that described in Example 29, 160 milliliters ofmethanol, 1.6 milliliters of 3 N sodium hydroxide, and 0.8 gram of 5percent palladium-on-charcoal was stirred at room temperature in anitrogen atmosphere. The hydrogen uptake stopped after 2 hours at whichtime520 milliliters had been adsorbed. After addition of 0.3 milliliterof acetic acid, the catalyst was filtered off and the filtrateevaporated to dryness to yield 4.9 grams of product consistingpredominantly of 6a,9a trans 3 ethyl 6a;3methyl-1,2,3,5,6,6a,7,8,9,9adecahydrocyclopenta [f] 1]benzopyran-7-ol.

EXAMPLE 42 Employing apparatus and procedures similar to those describedin Example 41, but substituting the product of Example 30 for that ofExample 29, there is produced predominantly 6a,9a trans 3,6a/9 diethyl1,2,3,5,6,6a,7, 8,9,9a-decahydrocyclopenta [f] [1]benzopyran-7-ol.

EXAMPLE 43 Employing apparatus and procedures similar to those describedin Example 41 but substituting the product of Example 31 for that ofExample 29, there is produced predominantly 6a,9a trans 3,6a 3dimethyl-1,2,3,5,6,6a, 7,8,9,9a-decahydrocyclopenta [f][1]benzopyran-7-ol.

36 EXAMPLE 44 1 Employing apparatus and procedures similar to thosedescribed in Example 41 but substituting the product of Example 32 forthat of Example 29, there 'isproduced predominantly 6a,9a trans 6a 3methyl-3-propyl-1,2,3, 5,6,6a,7,8,9,9adecahydrocyclopenta[f][llbenzopyran- 7-01.

EXAMPLE 45 Employing apparatus and procedures similar to those describedin Example 41 but substituting the product of Example 33 for that ofExample 29, there is produced predominantly 6a,10a trans 3 ethyl 6apmethyll,2,3,5,6,6a,8,9,l0,10a decahydro 7H naphtho[2,1-b] pyran-7-ol.

EXAMPLE 46 Employing apparatus and procedures similar to those describedin Example 41. but substituting the product of Example 34 for that ofExample 29, there is produced predominantly 6a,10a trans 3,6afldiethyl-1,2,3,5,6,6a, 8,9,10,10a decahydro 7H naphtho [2,1-b]pyran-7-o1.

EXAMPLE 47 The dienol of Example 35 was dissolvedin 50 milliliters oftoluene and then hydrogenated as described in Example 41, employing 378milligrams of a 5 percentpalladium-on-charcoal catalyst. After theuptake of l 11 milliliters of hydrogen, there was obtained 1.39 grams ofoptically active 6a,9a trans 3 pentyl 6a,? methyl- 1,2,3,5,6,6a,7,8,9,9adecahydrocyclopenta[f] [1]benzopyran-7-ol.

EXAMPLE 48 A solution of 7/3 acetoxy 3 (4 acetoxypentyl)-6a;8- methyl1,2,3,5,6,6a,7,8 octahydrocyclopenta[f] [1]benzopyran (1.31 g.;chromatographed) in toluene (50 ml.) was hydrogenated under normalconditions using 5 percent palladium-on-charcoal catalyst (262 mg). Theuptake (88 ml.) of hydrogen stopped after'5 hoursJThe workup byextraction with ether (3 times), washing of the combined extracts withsodium bicarbonate solution and water, drying over sodium sulfate,filtration, and evaporation of the filtrate at 50 C. in vacuo gave crude6a,9atrans 7,6 acetoxy 3 (4 acetoxypentyl)-6a;8-methyl-1,2,3,5,6,6a,7,8,9,9a decahydrocyclopenta[f] [llbenzopyran as an oil.

EXAMPLE 49 A solution of 11,11 ethylen'edioxy 7 hydroxy 1- dodecen 3 one(6.7 g.; prepared as described in Example 7) in 25 ml. of toluene wastreated with 2-methyl- 1,3 cyclopentadione (3.50 g.), pyridine (2.7m1.),.and hydroquinone (140 mg.), and the resulting mixture refluxed for8 hours using Dean-Stark apparatus.

At the end of the reflux period, the reaction mixture was chilled, the 2methyl 1,3 cyclopentadione removed by filtration, and the filtrateconcentrated in vacuo (water aspirator, 40 The crude product3-[4,4-(ethylenedioxy) pentyl] 1,2,3,5,6,6a hexahydro 6a'flmethylcyclopenta[f] [1]benzopyran 7 (8H) one (8.15 g.)waschromatographed on 82 g. of neutral alumina'Grade III and the columneluted with hexane-10% ether. The eluted fractions 2-10 contained thedesired product which was recrystallized once from isopropylether-hexane giving'almost colorless crystals of3-[4,4-(ethylenedioxy)pentyl']- 1,2,3,5,6,6a hexahydro 6afi'methylcyclopenta[f] [-1] benzopyran 7(8H) one, a sample of which uponbeing recrystallized from hexane-ether melted at 6972.

EXAMPLE so To lithium aluminum hydride (0.38 g.) in tetrahydro- 'furan(90 ml.) at 0, a solution of the 3 [4,4(ethylenedioxy)pentyl]-1,2,3,5,6,6a hexahydro 621 3methylcyclopenta[f][11benzopyran 7(8H) one (3.7 g.) in 75 ml.tetrahydrofuran was added over a period of 15 minutes.

Upon completion of the addition of 3-[4,4-(ethylenedioxy')pentyl]1,2,3,5,6,6a hexahydro 6a/8 methylcyclopen t a[f] [1]benZopyran7(8H)-one, the mixture was stirred at for 1 hour. A small amount ofwater was then added to the reaction mixture. Concentration of thereactionmixtu're in vacuo gave a' yellow liquid which crystaL lized uponstanding. The product, 3 [4,4 (ethylenedioxy)pentyl] 1,2,3,5,6,6a,7,8octahydro Gafi methylcyclopenta[f][1]benzopyran-7-o1 was collected byfiltration.

A sample of the product, after recrystallization four times from dilutemethanol and. once from ether-hexane,

melted at 91-93".

EXAMPLE 51 3 [4,4(ethylenedioxy)pentyl]-l,2,3,'6,6a,7,8-octahydro-6a/8-methylcyclopenta[f][l]benzopyran7-ol(10 g.) was dissolved in 250 ml. of toluene and hydrogenated in thepresence of 1.7 g. of 5% palladium-on-charcoal catalyst. During ca. 9hour period 710 ml. of H were consumed. The hydrogenation was performedat room temperature.

At the end of the reaction period the catalyst was removed byfiltration, and the solvent removed in vacuo. The crude product waschromatographed on 100 g. of neutral alumina Grade III, and the columneluted with hexane-ether (1:2) giving purified product, 6a,9a-trans-3-[4,4 (ethylenedioxy)pentyl]1,2,3,5,6,6a,7,8,9,9a-decahydro-6afi-methylcyclopenta [f[1]benzopyran-7-o1.

EXAMPLE 52 A mixture of 465 milligrams of 3-ethyl-6aB-methyl-1,2,3,5,6,-6a,8 hexahydrocyclopenta[f] [1]benzopyran 7 (8H)-one, asproduced in a manner similar to that described in Example 8, 20milliliters of toluene, and 150 milligrams of 5 percentpalladium-on-charcoal was hydrogenated under ambient conditions. Thehydrogen uptake ceased after one hour, after which time 50 millilitershad been adsorbed. After filtering the reaction mixture and evaporationof the filtrate, there was obtained the product monoenol ether as an oilcontaining predominantly6a,9a-cis-3-ethyL6afl-methyl-1,2,3,5,6,6a,'9,9a-octahydrocyclopenta [f]1 benzopyran-7 8H) -one.

.. EXAMPLE 53 Employing apparatus and procedures similar to thosedescribed in Example 52 but substituting the product of Example 19 forthat of Example 8, there is produced predominantly 6a,9acis-3,6afl-diethyl-1,2,3,5,6,6a,9,9a-octahydrocyclopenta [f] 1benzopyran-7 8H) -one.

EXAMPLE 5'4 Employing apparatus and procedures similar to thosedescribed in Example 52 but substituting the product of Example 22 forthat of Example 8, there is produced pr e dominantly 6a,9.a cis,3,GaB-dimethyl 1,2,3,5,6,6a,9,9a4 octahydrocyclopenta[f-1[.1]benzopyran-7 (8H)-onc.

Employing apparatus and procedures similar to those described in Example47 but substituting the product o f Example 23 forthat of Example7,-'there is produced predominantly 6a,9acis-6afi-methyl-3-propyl-1,2,3,5,6,6a,9, 9a-octahydrocyclopenta [f] l]benZ,0PYran-7 (8H) -one.

. E AM .Employingapparatusand-procedures similar to those described inExample 52 but substituting theproduct of Example 20 for that of Example8, there is produced predominantly 6a,10a cis3-ethyl-6aB-methyl-1,2,3,5,6,6a,8, 9,10,10a-decahydro-7H-naphtho[2,1:b]pyran-7-one.

38 EXAMPLE s7 Employing apparatus and procedures similar to thosedescribed in Example 52 but substituting the product of Example 21 forthat of Example 8, there is produced predominantly 6a,10a cis3,6al3-diethyl-l,2,3,5,6,6a,8,9,10,10a-decahydromaphtho[2,1-b]pyran-7-one.

EXAMPLE 58 A solution of the 4.9 grams of hydrogenation product obtainedin Example 41 in milliliters of acetone and 15 milliliters of 1 Nsulfuric acid was held at 25 C. for 30 minutes. After extraction of thereaction mixture with ether, washing with water and sodium bicarbonatesolution, drying over sodium sulfate, filtration and evaporation, therewas obtained 5.1 grams of crude 6a,9a-trans-3- ethyl 6afimethylperhydrocyclopenta [f] [1]benzopyran- 4a,7-diol. This product oncrystallization from an etherhexane mixture at 0 C. yielded 3.5 grams,melting point 1l3ll6 C. A second crop weighting 0.4 grams, melting point114-l17 C., was obtained from the mother liquor. The melting point wasincreased from 121-122.5 C. after several additional recrystallizations.

By employing similar procedures 'but substituting methanol or aceticacid for the water, there are obtained the corresponding 4a-methoxyand4a-acetoxy-derivatives, respectively.

EXAMPLE 59 Employing apparatus and procedures similar to those describedin Example 58 but substituting the product of Example 42 for that ofExample 41, there is produced predominantly 6a,9a-trans 3,6a5diethylperhydrocyclopenta[f] 1]benzopyran-4a,7-diol.

EXAMPLE 60 Employing apparatus and procedures similar to those describedin Example 5 8 but substituting the product of Example 43 for that ofExample 41, there is produced predominantly '6a,9atrans-3,6aB-dimethylperhydrocyclopenta[f] 1]benzopyran-4a,7-diol.

.EXAMPLE 61 Employing apparatus and procedures similar to thosedescribed in Example 58 but substituting the product of Example 44 forthat of Example 41, there is produced predominantly 6a,9atrans-6a/8-methyl-3-propylperhydrocyclopenta [f [l]benzopyran-4a,7-diol.

EXAMPLE 62 Employing apparatus and procedures similar to those describedin Example 58 but substituting the product of Example 45 for that ofExample 41, there is produced predominantly 6a,10atrans-3-ethyl-6a13-methylperhydronaphtho [2,1-b]pyran-4a,7-diol.

EXAMPLE 63 Employing apparatus and procedures similar to those describedin Example 58 but substituting the product of Example 46 for that ofExample 41, there is produced predominantly6a,10a-trans-3,6afi-diethylperhydronaphtho [2,l-b]pyran-4a,7-diol. 1

EXAMPLE 64 A 1.25-gram portion of the crude hydrogenation productobtained as described in Example 47 was dissolved in 25 milliliters ofacetone and treated With 1 N sulfuric acid as described in Example 58.After standing at 25 C. for 45 minutes and workup of the reactionmixture, there was obtained 1.20 grams of optically active6a,9a-trans-3.- pentyl 6a/3-methylperhydr0cyclopenta[f] [llbenzopyraii-4a,- 7-diol as an oil. 1

EXAMPLE 65 A solution of 6-[4-(t-butoxy)pentyl]-tetrahydropyran- 2-ol (5g.) in tetrahydrofuran (50 ml.) wasadded within 30 minutes at to asolution of vinyl magnesium chloride in tetrahydrofuran, prepared frommagnesium (2.0 g.) and 4 g. of vinyl chloride, dissolved intetrahydrofuran (50 ml.). After stirring overnight at room temperature,the reaction solution was treated with ammonium chloride-ice and thenextracted with chloroform (3 times, each time 100 ml.). The organicphase was washed with water, dried and evaporated in vacuo giving crude3,7-dihydroxy- 1l-(t-butoxy)-dodec-1-ene.

Crude 3,7-dihydroxy-11-(t-butoxy)-dodec-l-ene (5.8 g., prepared asdescribed above) was dissolved in benzene (200 ml.) and the reactionmixture was then stirred for 2 hours at 25 after addition of activatedmanganese dioxide (58 g.). Filtration and evaporation of the filtrate at30 in vacuo afforded crude 7-hydroxy-l1-(t-butoxy)- dodec-1-en-3-one.

EXAMPLE 66 A mixture of crude6a,9a-trans-7fl-acetoxy-3-(4-acetoxypentyl)-6afi-methyl-1,2,3,5,6,6a,7,8,9,9adecahydrocyclopenta[f] [1]benzopyran (1.3 g., obtained by the procedureof Example 48), acetone (30 ml.) and 1 N sulfuric acid (15 ml.) wasallowed to stand for 1 hour at room temperature. The workup byextraction with ether (3 times), washing of the combined extracts withsodium bicarbonate solution and water, drying over sodium sulfate,filtration, and evaporation of the filtrate at 50 C. in vacuo afiordedcrude 6a,9a-trans-3-(4-acetoxypentyl)- 7Bacetoxy-6aB-methylperhydrocyclopenta [f] [1]benzopyran-4a-ol, which waspurified by chromatography on alumina (67.5 g.). Fractions (68 ml. each)were taken as follows: 13=hexane-ether (9:1), 4-6=hexane-ether (4:1),7-9=hexane-ether (2:1) and -12=hexane-ether (1:1). Thin layerchromatography analysis showed fractions 4-10 (1.02 g. afterevaporation) to be pure 6a,9atrans-3-(4acetoxypentyl)Jp-acetoxy-6aB-methylperhydrocyclopenta [f] 1benzopyran-4a-ol.

EXAMPLE 67 6a,9a-trans 3 [4,4-(ethylenedioxy)pentyl]-1,2,3,5,6, 6a7,8,9,9a decahydro 6a 8 methylcyclopenta[f] [1] benzopyran-7-ol (9.04g., obtained and purified as described in Example 51) was dissolved inacetone (180 ml.) and to this solution 90 ml. of 1 N H SO was added. Thereaction mixture was allowed to remain at room temperature for 4 hoursbefore it was neutralized with sodium bicarbonate solution, diluted withca. 180 ml. of water, and extracted three times, each time with 200 ml.of chloroform,. The extract was washed three times with Water, dried,and the solvent removed to afiord a slightly pink-colored, viscousliquid.

This crude product was chromatographed on 240g. neutral aluminum GradeIII, and the column eluted with hexane-ether (1:2 and 1:9) followed bychloroformether (1:1). Several of the eluted fractions contained thedesired product, 6a,9a-trans-3-[4,4-(ethylenedioxy)pentyl] Gaflmethylperhydrocyclopenta[f] [1]benzopyran- 4a,7,B-diol.

EXAMPLE 68 Crude 7-hydroxy-1l-(t-butoxy)-dodec-1-en-3-one (4.6 g.,obtained as described in Example 65) was dissolved in toluene (46 m1.)and to this solution there was added 2-methylcyclopentane-1,3-dione (3g.), pyridine (4.6 ml.) and hydroquinone (100 mg.). The reaction mixturewas then refluxed for 8 hours, using a Dean-Stark water trap. The workupand chromatography purification was performed as described in Example 8and afforded 3-[4-(tbutoxy)-pentyl] 6a;8methyl-l,2,3,5,6,6a-hexahydrocyclopenta [f] [1]benzopyran-7 8H -one.

In order to remove the protective t-butylether group, a 1 g. sample ofthe product obtained above was refluxed for 5 hours under a nitrogenatmosphere in tetrahydrofuran (50 ml.) containing 10 ml. of 1 Nhydrochloric acid. Workup by extraction with ether, washing with waterand evaporation to dryness in vacuo at 60 yielded EXAMPLE 69 Employingapparatus and procedures similar to those described in Example 58 butsubstituting the ketone of Example 52 for the 7-01 of Example 41, thereis produced predominantly6a,9a-cis-3-ethyl-4a-hydroxy-6afimethylperhydrocyclopenta [f] 1benzopyran-7-one.

EXAMPLE 70 Employing apparatus and procedures similar to those describedin Example 58 but substituting the ketone of Example 53 for the diol ofExample 41, there is produced predominantly 6a,9acis-3,6a,8-diethyl-4a-hydroxyperhydrocyclopenta [f] 1]benzopyran-7-one.

EXAMPLE 71 Employing apparatus and procedures similar to those describedin Example 58 but substituting the ketone of Example 54 for the diol ofExample 41, there is produced predominantly6a,9a-cis-3,6afl-dimethyl-4a-hydroxyperhydrocyclopenta [f]1]benzopyran-7-one.

EXAMPLE 72 Employing apparatus and procedures similar to those describedin Example 58 but substituting the ketone of Example 56 for the diol ofExample 41, there is produced predominantly6a,10a-cis-3-ethyl-4a-hydroxy-6ap-methylperhydronaphtho 2,1-b]pyran-7-one.

EXAMPLE 73 Employing apparatus and procedures similar to those describedin Example 58 but substituting the ketone of Example 57 for the diol ofExample 41, there is produced predominantly6a,10a-cis-3,6aB-diethyl-4a-hydroxyperhydronaphtho[2,1-b]pyran-7-one.

EXAMPLE 74 A mixture of 117 milligrams of 3-ethyl-6afl-methyl-1,2,3,5,6,6a hexahydrocyclopenta[f] [l]benzopyran-7-0l produced in amanner similar to that described in Example 29, 10 milliliters ofisopropanol, 5 milliliters of 1 N sulfuric acid, and 20 milligrams of 5percent palladiumon-charcoal was hydrogenated at standard temperatureand pressure. Workup of the reaction product in the manner described inExample 58, followed by crystallization from an ether-hexane mixture,gave 64 milligrams of 6a,9a trans-3-ethyl-6afi-methylperhydrocyclopenta[f] [1] benzopyran-4a,7-diol, melting point 108-112" C.

By employing similar procedures, but substituting methanol or aceticacid for the water, there are obtained the corresponding 4a-methoxyand4a-acetoxy-derivatives, respectively.

EXAMPLE 75 A solution of 255 milligrams of 6a,9a-trans-3-ethyl- 6al3methylperhydrocyclopenta[f] [1]benzopyran 4a,7- diol produced asdescribed in Example 58 in 10 milliliters of dichloromethane was treatedwith a solution of 200 milligrams of chromic acid in 5 milliliters of 3N sulfuric acid and stirred at room temperature for 18 hours. Theresulting reaction mixture was worked up as described in Example 5 8 toyield a crude product which was purified by chromatography on silicagel. Recrystallization of the thus-recovered product from anether-hexane mixture yielded a sample of6a,9a-trans-3-ethyl-4a-hydroxy-6a,8-

